Cirrhosis Of Liver

Cirrhosis of the liver is a chronic and progressive liver disease characterized by the irreversible scarring of liver tissue. This scarring, or fibrosis, replaces healthy liver cells with non-functional scar tissue, leading to a distorted liver structure and impaired liver function. Over time, this damage can severely compromise the liver’s ability to perform its vital functions, potentially leading to liver failure, a life-threatening condition.

The biological basis of cirrhosis involves a complex and dynamic process initiated by chronic liver injury. Persistent damage from various causes, such as viral infections, excessive alcohol consumption, metabolic disorders, or autoimmune conditions, triggers sustained inflammation. This inflammation activates specialized liver cells, particularly hepatic stellate cells, which become fibrogenic and produce excessive amounts of extracellular matrix proteins, predominantly collagen. The accumulation of this scar tissue forms fibrous bands and regenerative nodules, disrupting the normal architecture and blood flow within the liver. Genetic factors are increasingly recognized as significant contributors to an individual’s susceptibility to and progression of liver cirrhosis. For example, genome-wide association studies (GWAS) have identified specific genetic loci associated with various forms of liver disease that can culminate in cirrhosis. The IL28B gene, for instance, has been found to have a major effect on hepatitis C virus (HCV) clearance, influencing the risk of HCV-related cirrhosis^[1]. Genetic modifiers have also been identified in liver disease associated with cystic fibrosis^[2]. In hereditary hemochromatosis, the PCSK7 gene has been highlighted as a host risk factor for liver cirrhosis ^[3]. For primary biliary cirrhosis (PBC), strong genetic associations have been found within the HLA class II region, involving genes such as HLA-DQB1, C6orf10, BTNL2, and HLA-DRA ^[4]. Other loci like IL12A, IL12RB2, STAT4, and CTLA4 have also shown associations with PBC ^[4]. Similarly, risk loci for primary sclerosing cholangitis (PSC) have been identified at GPR35 and TCF4 ^[5].

Clinically, cirrhosis can present with a wide spectrum of symptoms, ranging from non-specific manifestations like fatigue and jaundice to severe complications such as fluid retention (ascites), bleeding from esophageal varices, and hepatic encephalopathy. Diagnosis typically involves a combination of blood tests, imaging studies, and sometimes a liver biopsy. Early detection and aggressive management of the underlying cause are critical to slow or halt its progression. In advanced stages, where liver function is severely compromised, liver transplantation may be the only curative option.

Cirrhosis represents a significant global public health challenge, contributing to substantial morbidity and mortality worldwide. Its social importance is underscored by its profound impact on the quality of life for affected individuals and their families, as well as the considerable economic burden it places on healthcare systems through long-term care, hospitalizations, and lost productivity. A deeper understanding of the genetic predispositions and molecular pathways involved in cirrhosis is crucial for developing improved screening methods, targeted therapeutic interventions, and effective preventive strategies, ultimately aiming to mitigate the individual and societal toll of this devastating liver condition.

Limitations

Genetic studies of liver conditions, including cirrhosis, often face several limitations that can influence the interpretation and generalizability of their findings. These limitations span aspects of population diversity, the definition and measurement of the trait, and the statistical methodologies employed.

Population Specificity and Generalizability

Genetic association studies frequently focus on specific populations, which can limit the broader applicability of their findings. When studies are conducted predominantly within one ancestral group, such as individuals of European origin, the identified genetic variants and their effect sizes may not be directly transferable to other diverse populations ^[6]. This is due to differences in allele frequencies, linkage disequilibrium patterns, and varying environmental exposures across different ethnic groups, underscoring the need for more inclusive research to ensure equitable clinical translation. Genetic findings derived from a limited set of ancestries may therefore not fully capture the global genetic architecture of cirrhosis.

Phenotypic Definition and Scope

The precise definition and scope of the studied trait can constrain the interpretation of genetic findings. For instance, studies that specifically adhere to the criteria for primary biliary cirrhosis (PBC) ^[7], while ensuring diagnostic accuracy for that particular condition, may yield results that are highly specific to PBC and do not fully extend to other forms of cirrhosis with different underlying etiologies. Furthermore, relying on plasma liver enzyme levels (e.g., ALT, ALP, GGT) as quantitative traits provides valuable insights into liver health but represents surrogate markers rather than direct measures of liver fibrosis or the advanced stages of cirrhosis. This indirect assessment can limit the ability to identify genetic factors that specifically influence the progression of liver damage towards severe scarring or failure.

Methodological and Statistical Constraints

Genetic association studies, even when employing meta-analysis, inherently face methodological and statistical limitations. The power to detect genetic variants is often calibrated to identify those explaining a certain minimum percentage of population variation, meaning that variants with very small effect sizes or those involved in complex gene-gene or gene-environment interactions may be overlooked. This contributes to the phenomenon of “missing heritability,” where identified genetic factors account for only a fraction of the total genetic predisposition. The choice and coverage of genotyping arrays, such as Affymetrix or HumanHap platforms, can also influence the density of genetic markers analyzed, and the quality of imputation is critical for accurately inferring ungenotyped SNPs ^[8]; ^[9]. While sophisticated statistical methods, including adjustments for population substructure, are typically implemented ^[10], residual confounding can still occur, potentially affecting the robustness of reported associations.

Variants

Genetic variations play a crucial role in an individual’s susceptibility to liver diseases, including cirrhosis. These variants can influence gene function, protein activity, and metabolic pathways, ultimately impacting liver health. The following sections detail specific variants and their associated genes, highlighting their relevance to cirrhosis and related liver conditions.

The PNPLA3 gene, encoding patatin-like phospholipase domain-containing protein 3, is significantly involved in the metabolism of lipid droplets within liver cells. Variants such as rs738409 (I148M), rs738408 , and rs13056638 are particularly relevant. The rs738409 variant, a non-synonymous change from isoleucine to methionine at position 148, impairs the enzyme’s ability to hydrolyze triglycerides, leading to their accumulation in hepatocytes. This genetic alteration is strongly linked to the severity of non-alcoholic fatty liver disease (NAFLD)^[11], liver steatosis, and the progression of fibrosis. It is also a confirmed genetic risk factor for alcohol-related cirrhosis^[12]and plays a role in the development of hepatocellular carcinoma (HCC)^[13].

Another key gene is TM6SF2(Transmembrane 6 superfamily member 2), which plays a role in very-low-density lipoprotein (VLDL) secretion and lipid metabolism in the liver. Thers58542926 variant in TM6SF2 is associated with reduced VLDL secretion, causing triglycerides to accumulate in the liver and increasing susceptibility to NAFLD and its progression. This variant is recognized as a risk locus for alcohol-related cirrhosis and confers susceptibility to NAFLD and its histological severity ^[12]. The HSD17B13 gene, encoding hydroxysteroid 17-beta dehydrogenase 13, is an enzyme primarily expressed in the liver that metabolizes lipid derivatives. Variants like rs28636836 and rs11735092 are of interest, as certain loss-of-function alleles in HSD17B13have been associated with a reduced risk of NAFLD and its progression to advanced fibrosis and cirrhosis, suggesting a protective role.

The SERPINA1 gene produces alpha-1 antitrypsin (AAT), a protein vital for protecting tissues from inflammatory enzymes, particularly in the lungs and liver. The rs28929474 variant is a common severe deficiency allele (e.g., Z allele) that causes misfolded AAT protein to accumulate in liver cells, leading to liver damage, increased risk of cirrhosis, and hepatocellular carcinoma. Thers112635299 variant, located in an intergenic region between SERPINA2 and SERPINA1, may influence the expression levels of SERPINA1, thereby indirectly affecting AAT protein levels and liver health. The IFNL4gene encodes interferon lambda 4, a cytokine involved in the innate immune response, especially against viral infections like hepatitis C virus (HCV). Thers4803221 variant can influence the spontaneous clearance of HCV infection; unfavorable variants can lead to persistent HCV infection, accelerating the progression to liver fibrosis and cirrhosis.

The HLA-DQB1 gene, part of the major histocompatibility complex (MHC) class II, is critical for presenting antigens and orchestrating immune responses. The rs28746951 variant, found in an intergenic region between HLA-DQB1 and MTCO3P1, is located within the highly polymorphic HLA region. Variations here can influence immune recognition and contribute to the susceptibility of various autoimmune conditions, including those affecting the liver. The rs6834314 variant, an intergenic polymorphism between KLHL8 (Kelch-like family member 8) and MIR5705 (microRNA 5705), may influence the expression or regulation of nearby genes, potentially impacting cellular processes relevant to liver health. The SUGP1 gene (SURP and G-patch domain-containing protein 1) is involved in RNA splicing. The rs739846 variant could affect splicing efficiency or accuracy, potentially leading to altered protein production or cellular dysfunction that might indirectly contribute to liver pathology. Lastly, the MTARC1 gene (Mitochondrial amidoxime reducing component 1) plays a role in the liver’s detoxification processes. Variants such as rs2642438 and rs2642439 could alter the enzyme’s activity, influencing the liver’s capacity to metabolize certain drugs and toxins, which may increase oxidative stress and liver injury, thereby impacting cirrhosis risk.

Key Variants

RS ID	Gene	Related Traits
rs738409 rs738408 rs13056638	PNPLA3	non-alcoholic fatty liver disease serum alanine aminotransferase amount Red cell distribution width response to combination chemotherapy, serum alanine aminotransferase amount triacylglycerol 56:6 measurement
rs58542926	TM6SF2	triglyceride measurement total cholesterol measurement serum alanine aminotransferase amount serum albumin amount alkaline phosphatase measurement
rs28929474	SERPINA1	forced expiratory volume, response to bronchodilator FEV/FVC ratio, response to bronchodilator alcohol consumption quality heel bone mineral density serum alanine aminotransferase amount
rs6834314	KLHL8 - MIR5705	serum alanine aminotransferase amount aspartate aminotransferase measurement cirrhosis of liver
rs739846	SUGP1	aspartate aminotransferase measurement serum alanine aminotransferase amount liver fibrosis measurement triglyceride measurement, blood VLDL cholesterol amount free cholesterol measurement, blood VLDL cholesterol amount
rs2642438 rs2642439	MTARC1	high density lipoprotein cholesterol measurement alkaline phosphatase measurement total cholesterol measurement low density lipoprotein cholesterol measurement, alcohol consumption quality alcohol consumption quality, high density lipoprotein cholesterol measurement
rs28636836 rs11735092	HSD17B13	cirrhosis of liver
rs4803221	IFNL4	viral load cirrhosis of liver liver disease
rs112635299	SERPINA2 - SERPINA1	forced expiratory volume, response to bronchodilator FEV/FVC ratio, response to bronchodilator coronary artery disease BMI-adjusted waist circumference C-reactive protein measurement
rs28746951	HLA-DQB1 - MTCO3P1	cirrhosis of liver

Classification, Definition, and Terminology

Cirrhosis of the liver is the most advanced stage of liver fibrosis^[14]. It represents severe, irreversible scarring of the liver tissue, which can result from various chronic liver diseases, including Nonalcoholic Fatty Liver Disease (NAFLD)^[14].

Classification

In histological assessments of liver disease, cirrhosis is specifically classified asstage 4within the Brunt staging system for fibrosis^[14]. The Brunt system evaluates the progression of liver fibrosis through distinct stages:

• Stage 1:Characterized by perivenular and/or perisinusoidal fibrosis primarily in zone 3 of the liver.
• Stage 2:Involves combined pericellular portal fibrosis.
• Stage 3:Defined by the presence of septal or bridging fibrosis.
• Stage 4: Denotes cirrhosis ^[14].

This classification system is particularly utilized for evaluating advanced cases of NAFLD ^[14]. Additionally, “cryptogenic cirrhosis,” a form of chronic liver disease where the cause is unknown, is also recognized in clinical studies^[15].

Terminology

Understanding cirrhosis involves several related terms and measurements used in its assessment, diagnosis, and monitoring:

• Nonalcoholic Fatty Liver Disease (NAFLD):A condition characterized by fat accumulation in the liver, which can progress through stages of inflammation (NASH) and fibrosis to cirrhosis^[14].
• Fibrosis: The process of scarring in the liver, which, if left unchecked, can lead to cirrhosis ^[14].
• Liver Biopsy Features:Histopathological examination of liver tissue provides direct evidence of liver damage and fibrosis:
  • Brunt Grade: Assesses the severity of steatosis (fatty change), hepatocyte ballooning, and inflammation, typically graded from 1 to 3 ^[14].
  • Brunt Stage:Evaluates the extent of liver fibrosis, ranging from stage 1 to stage 4, with stage 4 representing cirrhosis^[14].
  • Fat Droplet: Quantifies the amount of fat deposition in the liver, categorized from 0 (<5%) to 4 (>67%) ^[14].
  • Iron Deposition: Categorizes the presence of free iron granules in the liver tissue, from 0 (absence) to 4 (identifiable at very low magnification) ^[14].
• Biochemical Traits:Blood tests that indicate liver function, inflammation, and metabolic status, often altered in liver disease:
  • AST (Aspartate Aminotransferase)
  • ALT (Alanine Transaminase)
  • GGT (Gamma-glutamyl transferase)
  • Albumin
  • Total bilirubin
  • Cholinesterase
  • Type IV collagen 7S
  • Hyaluronic acid
  • Triglycerides
  • Total cholesterol
  • IRI (Insulin)
  • FPG (Fasting Plasma Glucose)
  • hs-CRP (high-sensitivity C-reactive protein)
  • Adiponectin
  • Leptin
  • Ferritin
  • Uric acid
  • PLT (Platelets)
  • ANA (Antinuclear Antibodies)
• Clinical History:Co-existing medical conditions and historical diagnoses that are relevant to the development or progression of liver disease:
  • Diabetes (NGT/IGT/DM: Normal Glucose Tolerance/Impaired Glucose Tolerance/Diabetes Mellitus)
  • Hyperlipidemia
  • Hypertension
• Physical Measurement:Anthropometric data providing insights into body composition and metabolic health:
  • Amount of visceral fat (cm2)
  • Abdominal circumscription (cm)

Cirrhosis of the liver involves advanced liver fibrosis, and its assessment relies on specific measurement approaches and an understanding of variability in diagnosis.

Measurement Approaches

Liver biopsy is a method used to obtain histological findings for defining phenotypes of liver fibrosis^[16]. The METAVIR system provides an algorithm for grading activity in chronic hepatitis C, a condition that can lead to cirrhosis^[16].

Variability

The interpretation of liver biopsies can show variability both within a single observer (intraobserver variation) and between different observers (interobserver variation) in patients with chronic hepatitis C^[17]. Furthermore, the METAVIR system’s grading of activity in chronic hepatitis C is noted as being non-linear^[16], suggesting complexity in how disease progression is characterized.

Causes of Cirrhosis

Cirrhosis of the liver is a serious condition resulting from chronic liver damage, leading to scarring and impaired liver function. The development of cirrhosis is influenced by a combination of genetic predispositions and environmental exposures.

Genetic Factors

Genetic factors play a significant role in susceptibility to cirrhosis, often by influencing the risk of underlying liver diseases that can progress to cirrhosis:

• Primary Sclerosing Cholangitis (PSC): Genome-wide association studies (GWAS) have identified multiple genetic risk loci for PSC, a condition that can lead to cirrhosis. These include specific loci at GPR35 and TCF4, as well as nine additional risk loci located in immune-related disease regions^[18].
• Cystic Fibrosis (CF): Genetic modifiers have been identified that influence the severity of liver disease in individuals with cystic fibrosis, which can progress to cirrhosis^[2].
• Hereditary Hemochromatosis: The PCSK7 gene has been identified as a host risk factor for liver cirrhosis in hereditary hemochromatosis, a genetic disorder of iron metabolism ^[19].
• Primary Biliary Cirrhosis (PBC): Numerous genetic associations have been found for PBC, an autoimmune liver disease that causes cirrhosis:
  • HLA Region: Strong associations exist with human leukocyte antigen (HLA) alleles, particularly single nucleotide polymorphisms (SNPs) mapping to the region between theHLA-DQB1 and HLA-DQA2 genes (e.g., rs2856683 , rs9275312 , rs9275390 , rs7775228 ). Other genes within the HLA region, such as C6orf10 (with the strongest association signal), HLA-DPB1, BTNL2, and HLA-DRA, also show significant associations ^[20]. Specific SNPs like rs2395148 (C6orf10), rs3135363 (BTNL2), rs2856683 (HLA-DQB1), and rs9357152 (HLA-DQB1) account for the HLA-associated risk ^[20].
  • Non-HLA Loci: Significant associations have been observed with SNPs in the IL12A (e.g., rs6441286 , rs574808 ) and IL12RB2 (e.g., rs3790567 , rs3790565 ) loci. Other non-HLA loci include STAT4 (rs16833239 ), which is also linked to other autoimmune diseases, and CTLA4 (rs6748358 ) ^[20]. Additional variants at IRF5-TNPO3, 17q12–21, and MMEL1 are associated with PBC ^[21].
• Hepatitis C Virus (HCV) Progression: Genetic variations can influence the progression of HCV infection to severe fibrosis and cirrhosis. A panel of SNPs has been identified that may predict the risk of developing cirrhosis^[22]. Variants in the IFNGR2gene are associated with progression to severe fibrosis^[22]. A cluster of SNPs in the IL28B gene has a significant impact on HCV clearance, both spontaneous and treatment-induced, indirectly affecting the risk of cirrhosis ^[22].

Environmental Factors

Environmental factors can trigger or contribute to liver injury, potentially leading to cirrhosis:

• Drug-Induced Liver Injury (DILI): Certain medications can cause liver damage that may progress to cirrhosis. Genetic factors, particularly specific HLA alleles, often influence an individual’s susceptibility to DILI:
  • Lumiracoxib: Liver injury caused by lumiracoxib has been associated with specific HLA alleles ^[23].
  • Lapatinib: The HLA-DQA102:01 allele is a significant risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer^[24].
  • Ticlopidine: Ticlopidine-induced hepatotoxicity is linked to specific human leukocyte antigen genomic subtypes in Japanese patients ^[25].
  • Some drug-induced hepatic adverse events may have an underlying immune pathogenesis, even without overt clinical signs of immunopathology ^[26].
• Primary Biliary Cirrhosis (PBC): Environmental factors are considered to play a role in the development of PBC ^[27].

Biological Background

Cirrhosis represents the advanced and irreversible stage of various chronic liver diseases, fundamentally characterized by widespread liver fibrosis^[28]. Liver fibrosis is a pathological process involving the excessive accumulation of extracellular matrix proteins, which, if left unchecked, leads to the architectural distortion of the liver and the formation of regenerative nodules, ultimately culminating in cirrhosis^[29]. This progression is driven by complex molecular and cellular pathways, influenced by a combination of environmental factors and an individual’s genetic predisposition ^[30].

Genetic factors significantly contribute to both susceptibility and progression of liver fibrosis and cirrhosis. For instance, chronic infection with the Hepatitis C virus (HCV), particularly genotype 3, is a recognized driver of liver fibrosis progression^[7]. Studies have identified specific gene variants and panels of single nucleotide polymorphisms (SNPs) that can predict the risk of developing advanced fibrosis or cirrhosis in patients with chronic hepatitis C^[31][32]. A notable example includes variants in the Interferon gamma receptor 2 (IFNGR2) gene, which have been associated with progression to severe fibrosis in chronic hepatitis C infection, implicating the interferon-gamma signaling pathway in this process^[33]. Genome-wide association (GWA) studies have also been instrumental in uncovering genetic factors influencing HCV outcomes, such as a SNP cluster in the IL28B gene that significantly affects HCV clearance ^[5].

Beyond viral etiologies, other conditions lead to cirrhosis through distinct biological mechanisms. Hereditary hemochromatosis, an iron metabolism disorder, can result in cirrhosis, with the PCSK7 gene identified as a host risk factor ^[3]. Cholestatic liver diseases, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), involve damage to the bile ducts, leading to biliary fibrosis^[34][4]. These conditions primarily affect cholangiocytes, the epithelial cells lining the bile ducts ^[35]. Furthermore, genetic modifiers play a role in the severity of liver disease observed in conditions like cystic fibrosis^[2]. The development of primary biliary cirrhosis, for example, is influenced by a complex interplay of genetic, epigenetic, and environmental factors ^[30].

Pathways and Mechanisms

Liver cirrhosis can arise from various underlying molecular and physiological mechanisms. One significant pathway involves autoimmune processes, particularly observed in primary biliary cirrhosis (PBC), which is characterized as an autoimmune liver disease^[36].

Disruptions in iron metabolism also contribute to liver cirrhosis. For instance, in hereditary hemochromatosis, the gene PCSK7 has been identified as a host risk factor for the development of liver cirrhosis ^[3].

Environmental factors, such as exposure to xenobiotics, can initiate liver damage leading to cirrhosis. A mouse model has demonstrated that xenobiotic exposure can induce sclerosing cholangitis and subsequent biliary fibrosis, a precursor to cirrhosis^[37].

Furthermore, genetic modifiers play a role in the progression of liver disease in conditions like cystic fibrosis, influencing the development of liver complications^[2]. Cholestatic liver diseases, as a broader category, are also recognized for their potential to lead to cirrhosis ^[34].

Clinical Relevance

Cirrhosis of the liver represents the end-stage of various chronic liver diseases, necessitating accurate assessment for patient management.

The development of liver fibrosis and cirrhosis in conditions like chronic hepatitis C virus (HCV) infection involves host genetic factors^[28]. Identifying these genetic influences holds clinical relevance for risk stratification and prognosis.

Several genetic associations have been identified. Specific gene variants are associated with an increased risk of advanced fibrosis in patients with chronic hepatitis C^[31]. A 7-gene signature has been shown to identify the risk of developing cirrhosis in patients with chronic hepatitis C^[32]. Variants in the Interferon gamma receptor 2 gene have also been linked to liver fibrosis in chronic hepatitis C infection^[33]. Beyond fibrosis and cirrhosis risk, genetic factors such as IL28B, HLA-C, and KIR variants predict response to therapy in chronic HCV^[38].

Cirrhosis can also arise from other conditions. Hereditary hemochromatosis, an iron metabolism disorder, has a host risk factor (PCSK7) identified for liver cirrhosis ^[19]. Liver disease can be a complication in cystic fibrosis^[2]. Primary sclerosing cholangitis (PSC) can progress to severe liver failure and death, often requiring liver transplantation ^[5].

Diagnostic and assessment tools, such as the METAVIR scoring system, are used for grading activity and fibrosis in chronic hepatitis C, assisting in liver biopsy interpretation and understanding the natural history of fibrosis progression^[16]. The ability to identify genetic markers for cirrhosis development is crucial for timely medical intervention, risk stratification, and personalized treatment strategies to prevent end-stage liver disease.

Frequently Asked Questions About Cirrhosis Of Liver

These questions address the most important and specific aspects of cirrhosis of liver based on current genetic research.

---

1. My parent has cirrhosis. Am I likely to get it too?

Yes, there can be a genetic component that increases your susceptibility. While cirrhosis often has environmental triggers like alcohol or viruses, your genes can influence how your liver responds to injury. For conditions like hereditary hemochromatosis or certain autoimmune liver diseases, having a parent with the condition significantly raises your risk due to shared genetic predispositions.

2. Why did my friend clear Hepatitis C, but I got cirrhosis from it?

That’s a great question, and genetics play a big role. Variations in genes like IL28B have been shown to significantly affect how well your body clears the Hepatitis C virus. If you have certain versions of this gene, your immune system might be less effective at fighting off the infection, making you more prone to chronic infection and eventually cirrhosis compared to someone with different genetic variants.

3. Does my family’s background make me more prone to liver problems?

Yes, your ancestral background can influence your risk. Genetic studies often focus on specific populations, and the genetic variants identified might not apply equally to all ethnic groups due to differences in gene frequencies and environmental exposures. This means that certain populations might have unique genetic predispositions or protections against specific types of liver cirrhosis.

4. I have cystic fibrosis. Is my liver at higher risk because of my genes?

Unfortunately, yes. While cystic fibrosis primarily affects the lungs and digestive system, genetic modifiers have been identified that specifically increase the risk of liver disease in individuals with CF. These genetic variations can influence how your liver handles bile flow and inflammation, making it more vulnerable to damage and the development of cirrhosis over time.

5. Why do some people get autoimmune liver diseases like PBC, and others don’t?

Autoimmune liver diseases like Primary Biliary Cirrhosis (PBC) have strong genetic links. Your immune system’s genetic makeup, particularly genes in the HLA class II region like HLA-DQB1, C6orf10, BTNL2, and HLA-DRA, plays a crucial role. Other genes such as IL12A, IL12RB2, STAT4, and CTLA4 also contribute to this susceptibility, influencing how your immune system mistakenly attacks liver cells.

6. I have too much iron. Does that mean my liver will get cirrhosis?

Having too much iron, often due to hereditary hemochromatosis, does increase your risk. Your genes influence how your body processes iron, and specific variants, such as those in the PCSK7 gene, have been identified as risk factors for developing liver cirrhosis in individuals with hemochromatosis. This genetic predisposition means your liver is more susceptible to damage from iron overload.

7. Can genes explain why my liver damage progresses faster than someone else’s?

Absolutely. Genetic factors are increasingly recognized as significant contributors not just to whether you get cirrhosis, but also to how quickly it progresses. Your unique genetic profile can influence how your liver responds to injury, how efficiently it repairs itself, and the extent of inflammation and scarring that occurs, leading to varying rates of disease progression among individuals.

8. If I drink alcohol, will my liver be affected differently than my friend’s?

It’s very possible. While excessive alcohol consumption is a major cause of cirrhosis, an individual’s genetic makeup can influence their susceptibility to alcohol-induced liver damage. Some people may have genetic variations that make their liver more vulnerable to injury and scarring from alcohol, while others might tolerate similar amounts with less severe consequences, though no amount of excessive drinking is truly safe.

9. Is it worth getting a genetic test to understand my liver risk?

For certain specific conditions, a genetic test can be very informative. For example, if there’s a family history of conditions like hereditary hemochromatosis, primary biliary cirrhosis, or cystic fibrosis-related liver disease, genetic testing can identify specific risk variants. This knowledge can help guide personalized monitoring and preventive strategies, though general screening for all types of cirrhosis isn’t standard practice yet.

10. Why do some people get a rare liver disease called PSC, but not others?

Primary sclerosing cholangitis (PSC) has a strong genetic component that makes some individuals more susceptible. Specific genetic risk loci, like those found at GPR35 and TCF4, have been identified through genome-wide association studies. These genes influence immune responses and liver inflammation, increasing the likelihood that certain individuals will develop this rare autoimmune liver disease.

---

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Liu, J.Z., et al. “Dense Genotyping of Immune-Related Disease Regions Identifies Nine New Risk Loci for Primary Sclerosing Cholangitis.”Nature Genetics, vol. 45, 2013, pp. 670–675.

[2] Bartlett, J. R., et al. “Genetic Modifiers of Liver Disease in Cystic Fibrosis.”JAMA, vol. 302, 2009, pp. 1076–83.

[3] Stickel, F., et al. “Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis.” Human Molecular Genetics, vol. 23, 2014, pp. 3883–90.

[4] Kaplan, M. M., and M. E. Gershwin. “Primary Biliary Cirrhosis.” New England Journal of Medicine, vol. 353, 2005, pp. 1261–73.

[5] Ellinghaus, D., et al. “Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4.”Hepatology, vol. 58, 2013, pp. 1074–1083.

[6] Yamaguchi-Kabata, Y., Nakazono, K., Takahashi, A., Saito, S., Hosono, N., Kubo, M., Nakamura, Y., and Kamatani, N. “Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies.” Am. J. Hum. Genet., vol. 83, 2008, pp. 445–456.

[7] Lindor, K. D., et al. “Primary Biliary Cirrhosis.” Hepatology, vol. 50, 2009, pp. 291–.

[8] Hoffmann, T.J., Kvale, M.N., Hesselson, S.E., Zhan, Y., Aquino, C., Cao, Y., Cawley, S., Chung, E., Connell, S., Eshragh, J., et al. “Next generation genome-wide association tool: design and coverage of a high-throughput European-optimized SNP array.” Genomics, vol. 98, 2011, pp. 79–89.

[9] Nishida, N., Koike, A., Tajima, A., Ogasawara, Y., Ishibashi, Y., Uehara, Y., Inoue, I., and Tokunaga, K. “Evaluating the performance of Affymetrix SNP Array 6.0 platform with 400 Japanese individuals.” BMC Genomics, vol. 9, 2008, p. 431.

[10] Willer, C.J., Li, Y., and Abecasis, G.R. “METAL: fast and efficient meta-analysis of genomewide association scans.” Bioinformatics, vol. 26, 2010, pp. 2190–2191.

[11] Kawaguchi, T., et al. “Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease.”

[12] Buch, S., et al. “A Genome-Wide Association Study Confirms PNPLA3 and Identifies TM6SF2 and MBOAT7 as Risk Loci for Alcohol-Related Cirrhosis.” J Hepatol.

[13] Valenti, L., et al. “PNPLA3 I148M Variant and Hepatocellular Carcinoma: A Common Genetic Variant for a Rare Disease.”Dig Liver Dis Off J Ital Soc Gastroen.

[14] Brunt, Elizabeth M., et al. “Classification of Histological Grade and Fibrosis Stage in Advanced NAFLD Cases.”

[15] NASH CRN (National Institute of Diabetes and Digestive and Kidney Diseases funded). “NAFLD Database Study.”

[16] Bedossa, P., and T. Poynard. “An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group.”Hepatology, vol. 24, 1996, pp. 289–93.

[17] The METAVIR Cooperative Study Group. “Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C.”Hepatology, vol. 20, 1994, pp. 15–20.

[18] Karlsen, Tom H., et al. “Extended Analysis of a Genome-Wide Association Study in Primary Sclerosing Cholangitis Detects Multiple Novel Risk Loci.” Journal of Hepatology, vol. 57, 2012, pp. 366–75.

[19] Stickel, F., et al. “Evaluation of Genome-Wide Loci of Iron Metabolism in Hereditary Hemochromatosis Identifies PCSK7 as a Host Risk Factor of Liver Cirrhosis.” Human Molecular Genetics.

[20] Hirschfield, Gideon M., et al. “Genome-Wide Association Study of Primary Biliary Cirrhosis: Independent Roles for HLA and Non-HLA Variants.” New England Journal of Medicine, vol. 360, 2009, pp. 2544–55.

[21] Hirschfield, Gideon M., et al. “Variants at IRF5-TNPO3, 17q12–21 and MMEL1 are associated with primary biliary cirrhosis.” Nature Genetics, vol. 42, 2010, pp. 655–57.

[22] Lucena, M., et al. “Gastroenterology.” Author manuscript; available in PMC, 2012 July 1.

[23] Singer, Jeffrey B., et al. “A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury.” Nature Genetics, vol. 42, 2010, pp. 711–14.

[24] Spraggs, C. F., et al. “HLA-DQA1*02:01 Is a Major Risk Factor for Lapatinib-Induced Hepatotoxicity in Women With Advanced Breast Cancer.”Journal of Clinical Oncology, vol. 29, 2011, pp. 667–73.

[25] Hirata, K., et al. “Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study.” Pharmacogenomics Journal, vol. 8, 2008, pp. 29–33.

[26] Kindmark, Anders, et al. “Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis.” Pharmacogenomics Journal, vol. 8, 2008, pp. 186–95.

[27] Selmi, Carlo, and M. Eric Gershwin. “The role of environmental factors in primary biliary cirrhosis.” Trends in Immunology, vol. 30, 2009, pp. 415–20.

[28] Osterreicher, C. H., et al. “Genomics of Liver Fibrosis and Cirrhosis.”Seminars in Liver Disease, vol. 27, 2007, pp. 28–43.

[29] Bataller, R., et al. “Genetic Polymorphisms and the Progression of Liver Fibrosis: A Critical Appraisal.”Hepatology, vol. 37, 2003, pp. 493–503.

[30] Selmi, C., et al. “Primary Biliary Cirrhosis in Monozygotic and Dizygotic Twins: Genetics, Epigenetics, and Environment.” Gastroenterology, vol. 127, 2004, pp. 485–492.

[31] Huang, H., et al. “Identification of Two Gene Variants Associated with Risk of Advanced Fibrosis in Patients with Chronic Hepatitis C.”Gastroenterology, vol. 130, 2006, pp. 1679–87.

[32] Huang, H., et al. “A 7 Gene Signature Identifies the Risk of Developing Cirrhosis in Patients with Chronic Hepatitis C.”Hepatology, vol. 46, 2007, pp. 297–306.

[33] Nalpas, B., et al. “Interferon Gamma Receptor 2 Gene Variants Are Associated with Liver Fibrosis in Patients with Chronic Hepatitis C Infection.”Gut, vol. 59, 2010, pp. 1120–6.

[34] European Association for the Study of the Liver. “EASL Clinical Practice Guidelines: management of cholestatic liver diseases.” Journal of Hepatology, vol. 51, 2009, pp. 237–67.

[35] Sampaziotis, F., et al. “Cholangiocytes Derived from Human Induced Pluripotent Stem Cells for Disease Modeling and Drug Validation.”Nature Biotechnology, vol. 33, 2015, pp. 845–52.

[36] Cordell, H. J., et al. “International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.” Nature Communications, 22 Sep. 2015.

[37] Fickert, P., et al. “A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis.”American Journal of Pathology, vol. 171, 2007, pp. 525–36.

[38] Suppiah, V., et al. “IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study.”PLoS Medicine, vol. 8, no. 10, 2011, e1001092.