Robert Gish, MD, is the Medical Director of the Hepatitis B Foundation in Doylestown, Pennsylvania. He is an Adjunct Professor of Medicine at the University of Nevada School of Medicine in Las Vegas. He serves as an Adjunct Professor of Pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD, a Clinical Professor of Medicine at Loma Linda University. In addition, he is the Medical Director of the American Pacific Health Foundation.

Robert Gish, MD

Genetic Testing in Liver Disease: Interpreting Results and Clinical Impact

As genetic testing becomes more integrated into hepatology, clinicians are increasingly faced with challenges regarding how to interpret results and incorporate them into a broader diagnostic framework. In this segment of 

Liver Lineup: Updates & Unfiltered Insights

, guests Robert Gish, MD, and Saul Karpen, MD, PhD, explore the complexities of genetic interpretation, the evolving role of multidisciplinary evaluation, and how traditional tools like biopsy remain essential in the era of genomics.

Genetic panels often require clinical correlation, especially when results return as variants of uncertain significance

“Synergistic heterozygosity” may explain disease when multiple variants are present rather than a single mutation

Genetic testing can uncover rare, actionable diagnoses such as lysosomal acid lipase deficiency

Liver biopsy remains critical when genetic results are inconclusive or do not fully explain the clinical picture

Referral to genetics is most useful for targeted cases, including rare diseases and reproductive counseling

Whole-exome sequencing may be needed when standard panels are unrevealing but suspicion for genetic disease remains

Gish highlighted the limitations of relying solely on genetics, noting that referrals to major academic centers for additional interpretation often yield limited new insights unless more expansive approaches, such as whole-exome or whole-genome sequencing, are pursued. Instead, he has shifted toward a more selective and clinically driven use of genetic consultation, reserving referrals for targeted scenarios such as rare diagnoses, complex counseling questions, or reproductive planning.

At the same time, genetic testing can uncover unexpected and actionable findings. Gish described a patient with atypical cholestatic liver disease who was ultimately diagnosed with lysosomal acid lipase deficiency, a rare condition that would have been difficult to identify without genetic evaluation. In another case, identification of dual heterozygous variants helped explain overlapping pulmonary and hepatic disease, reinforcing the concept that multiple genetic factors can interact to shape clinical presentation.

This concept, referred to as “synergistic heterozygosity,” is gaining increasing recognition in hepatology. Rather than a single causative mutation, patients may harbor multiple variants that collectively contribute to disease. This paradigm challenges traditional binary thinking and underscores the importance of interpreting genetic results in clinical context.

A major continued barrier to adoption, however, is the interpretation of variants of uncertain significance (VUS). Gish argued that this terminology can be misleading and counterproductive, preferring instead a more pragmatic approach that emphasizes clinical correlation. For hepatologists, this means integrating genetic findings with other core elements of liver disease evaluation, including laboratory testing, imaging, and histology.

Indeed, both Gish and Karpen emphasized that genetic testing should complement established diagnostic tools rather than replace them. Liver biopsy, in particular, continues to play a critical role, especially when genetic findings are inconclusive. Histologic evidence of cholangiopathy or other structural abnormalities can help validate the clinical relevance of a genetic variant and, in some cases, contribute to its reclassification as pathogenic.

Karpen also highlighted the dynamic nature of genetic interpretation. A result considered inconclusive today may be better understood in the future as additional data emerge. In some cases, reanalysis of prior genetic testing has led to new diagnoses, reflecting the rapidly evolving knowledge base in genomics.

Editors’ note: Relevant disclosures for Reau include AbbVie, Gilead, Salix, Arbutus, and VIR. Relevant disclosures for Brown include Mallinckrodt Pharmaceuticals, Gilead, Salix, Intercept, Ipsen, and Madrigal. Relevant disclosures for Karpen include Mirum and Ipsen. Relevant disclosures for Gish include Abbott, AbbVie, Aligos, Altimmune, Arrowhead, AstraZeneca, Corcept, Genentech, Gilead Sciences, GSK, Intercept, Janssen, Merck, Perspectum, Pfizer, and others.

Videos

Experts discuss interpreting genetic testing in liver disease, the role of biopsy, and how to integrate variants into clinical decision-making.

Putting the Pieces Together: Genetic Testing, Biopsy, and Clinical Judgment

Expanding the Role of Genetic Testing in Liver Disease

Genetic testing is increasingly finding a place in the hepatology toolkit, but questions remain about who to test and when these panels offer the greatest clinical value. In this segment from an episode of 

, Robert Gish, MD, provides practical guidance rooted in real-world experience, highlighting how genetic testing can uncover hidden drivers of liver disease across a range of clinical scenarios.

 - Drug‑induced cholestasis & pregnancy

 - Case: COPD + dual heterozygote (CFTR + Alpha‑1)

 - Case: PEX mutation & transition to broader practice

Drawing on his experience ordering more than 80 genetic panels, Gish emphasized a broad, pragmatic approach. Rather than limiting testing to classic cholestatic presentations, he applies genetic evaluation to patients with unexplained liver disease more generally, including those with hepatocellular patterns of injury, reflecting a growing recognition that genetic contributions to liver disease are not always limited to traditional phenotypes.

However, he notes that certain clinical presentations should raise particular suspicion. Patients with antimitochondrial antibody-negative primary biliary cholangitis, lean metabolic dysfunction-associated steatotic liver disease accompanied by pruritus, or atypical biochemical patterns such as elevated alkaline phosphatase with normal gamma-glutamyl transferase may warrant genetic evaluation. These features can point toward underlying transporter defects, including variants associated with progressive familial intrahepatic cholestasis.

Gish also underscored the relevance of genetic testing in drug-induced cholestasis and intrahepatic cholestasis of pregnancy. In one case, a young pregnant patient with pruritus and fluctuating liver enzymes was found to carry variants in 

 and a bile acid synthesis gene. While her laboratory values normalized without treatment, the identification of these variants provided critical context for monitoring and risk assessment as her pregnancy progressed. Rather than relying solely on standard biomarkers, her care plan incorporated periodic liver tests and bile acid monitoring, reflecting a more personalized approach.

In another patient with severe pulmonary disease disproportionate to smoking history, genetic testing revealed heterozygous variants linked to cystic fibrosis and alpha-1 antitrypsin deficiency, offering a unifying explanation for both pulmonary and hepatic findings. In a separate case, identification of a mutation associated with a rare metabolic disorder prompted targeted follow-up testing, demonstrating how genetic panels can guide downstream diagnostic pathways.

Importantly, Gish noted that most patients tested will have ≥ 1 genetic variants. The challenge, therefore, lies not in detection but in interpretation, reinforcing the need for hepatologists to become comfortable navigating genetic data, even when results are not definitive.

As this discussion makes clear, genetic testing is no longer reserved for rare or pediatric cases. When used thoughtfully, it can provide meaningful insights into otherwise unexplained liver disease, helping clinicians refine diagnoses and tailor management strategies in an increasingly complex clinical landscape.

Editors’ note: Relevant disclosures for 

 include AbbVie, Gilead, Salix, Arbutus, and VIR. Relevant disclosures for 

 include Mallinckrodt Pharmaceuticals, Gilead, Salix, Intercept, Ipsen, and Madrigal. Relevant disclosures for 

 include Mirum and Ipsen. Relevant disclosures for 

 include Abbott, AbbVie, Aligos, Altimmune, Arrowhead, AstraZeneca, Corcept, Genentech, Gilead Sciences, GSK, Intercept, Janssen, Merck, Perspectum, Pfizer, and others.

In this segment of Liver Lineup, experts discuss genetic testing in cholestatic disease, highlighting real-world cases demonstrating the value of these tests.

Genetic Panels in Hepatology: Identifying the Right Patients

Liver Lineup: Navigating Genetic Testing in Cholestatic Liver Disease

Genetic testing is rapidly reshaping the diagnostic and therapeutic landscape of 

, but for many practicing hepatologists, its clinical application remains uncertain. In the latest episode of Liver Lineup, hosts Nancy Reau, MD, and Kimberly Brown, MD, are joined by Saul Karpen, MD, PhD, inaugural chief scientific officer for the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University and president of AASLD, and Robert Gish, MD, medical director of the Hepatitis B Foundation and the American Pacific Health Foundation, to unpack the evolving role of genetic testing in cholestatic disorders and provide practical guidance for integrating these tools into routine care.

Karpen, a pediatric hepatologist with decades of experience in cholestasis, outlined the historical arc of genetic testing in liver disease. Early approaches were laborious and limited, often requiring single-gene sequencing following invasive biopsies and yielding inconclusive results. However, advances over the past decade, particularly the advent of exome-based sequencing panels, have enabled clinicians to assess dozens of relevant genes simultaneously.

This shift has transformed genetic testing from a niche diagnostic tool into a foundational component of pediatric hepatology. Today, Karpen emphasized, such panels are “part of the fabric” of clinical evaluation in children with unexplained cholestasis.

For adult hepatologists, adoption has been slower, in part due to differences in clinical expectations. While pediatric providers may accept a modest diagnostic yield, adult clinicians often seek higher certainty before ordering specialized tests. Yet, as Gish highlighted, this mindset may need to evolve.

Drawing on his own experience ordering genetic panels, he noted that the majority of patients demonstrate ≥ 1 genetic variants, findings that can meaningfully inform diagnosis, risk stratification, and management.

Both experts emphasized that genetic testing should not be reserved solely for rare or refractory cases. Instead, it should be considered in a range of clinical scenarios, including unexplained cholestatic or mixed-pattern liver enzyme abnormalities, antimitochondrial antibody (AMA)-negative 

, atypical drug-induced liver injury, intrahepatic cholestasis of pregnancy, and even lean 

metabolic dysfunction-associated steatotic liver disease (MASLD)

. Importantly, these tests can uncover underlying genetic susceptibilities that may not have been clinically apparent.

A key challenge, however, lies in interpretation. Results frequently include variants of uncertain significance (VUS), which can create confusion and anxiety for both clinicians and patients. Karpen and Gish acknowledged this limitation but stressed that uncertainty is not unique to genetics—hepatologists routinely navigate ambiguous findings in imaging, histology, and laboratory testing. The critical step is correlating genetic results with the clinical phenotype, using them as one piece of a broader diagnostic puzzle.

Among the most clinically relevant genes discussed were 

, both of which play central roles in bile formation and transport. Variants in these genes can predispose patients to a spectrum of cholestatic conditions, sometimes manifesting only under physiologic stressors such as pregnancy, infection, or medication exposure. Notably, even heterozygous variants, traditionally considered benign, may contribute to disease in certain contexts, underscoring the concept of “synergistic heterozygosity.”

The conversation also highlighted the growing therapeutic implications of genetic insights. Identification of specific variants may guide treatment decisions, including the use of ursodeoxycholic acid or newer agents such as ileal bile acid transporter (IBAT) inhibitors. In some cases, genetic findings can explain treatment resistance or predict response, enabling more personalized care.

Despite these advances, both speakers agreed that collaboration remains essential. While geneticists can provide valuable support, particularly for complex cases requiring whole-exome sequencing, hepatologists must develop a working knowledge of key genes and interpretation principles. As Karpen noted, the field is still evolving, and variant classifications may change over time as new data emerge.

Hasegawa S, Yoneda M, Kurita Y, et al. Cholestatic Liver Disease: Current Treatment Strategies and New Therapeutic Agents. 

. 2021;81(10):1181-1192. doi:10.1007/s40265-021-01545-7

Brooks A. FDA Approves Linerixibat (Lynavoy) As First Treatment for Cholestatic Pruritus in PBC. HCPLive. March 19, 2026. Accessed April 7, 2026. 

https://www.hcplive.com/view/fda-approves-linerixibat-lynavoy-as-first-treatment-for-cholestatic-pruritus-in-pbc

Podcasts

Experts discuss when to use genetic testing in cholestatic disease, how to interpret results, and its growing role in diagnosis and management.

In 2013, Dr. Gish joined the consulting faculty at La Maestra in San Diego, California, to establish a liver care program in the Federally Qualified Health Care clinic. His integral role in the diagnosis, treatment and management of patients with NAFLD and NASH provides valuable guidance for this specialized sector of patient care.

Among the diseases that impact Americans and their caregivers, non-alcoholic fatty liver disease (NAFLD), also referred to as metabolic associated fatty liver disease (MAFLD), is gaining more attention. An umbrella term for a range of liver conditions affecting people who drink little to no alcohol, NAFLD affects approximately 

 individuals in the United States. The prevalence for its more serious form, non-alcoholic steatohepatitis (NASH), is expected to increase by 

In some cases, NASH may lead to cirrhosis, liver cancer, liver transplant and death. NASH, which is associated with nonspecific symptoms, and is often underdiagnosed and underreported, recently became the most 

 for a liver transplant in women and older patients.

Most patients with NASH experience few specific symptoms, especially in the early stages of the disease. When a patient feels well or has vague symptoms, it can be challenging for physicians and caregivers to convince the patient that they may have a dangerous condition.

Community health centers, which deliver exceptional care to medically underserved populations, share a common goal of providing coordinated, culturally competent and community-directed primary and preventive health care services. Today they deliver care to 

Physicians at community health centers play a critical role in not only helping to educate patients about the importance of liver for overall health, but also identifying the best approaches for preventing the progression of NAFLD.

 for developing NAFLD or NASH have obesity, type 2 diabetes (T2D), hyperlipidemia and/or metabolic syndrome. 

 are disproportionately affected by NAFLD, depending on genetic factors, access to health care or the prevalence of chronic diseases, such as metabolic syndrome or diabetes.

 of chronic conditions than the general population. This is important to note because the presence of T2D accelerates the progression of liver disease in patients with NAFLD, and NAFLD is an 

independent predictor associated with a more than two-fold

Researchers have found NAFLD, hepatitis C, liver cancer and liver transplants are prevalent in 

 of people who have T2D and in 30-90% of people who are obese. Being overweight or obese is responsible for about 

Because NAFLD and NASH are so tightly intertwined with obesity, diabetes and lifestyle, a “whole person” approach to patient engagement is needed to support behavioral changes that will result in better outcomes across the co-morbid conditions affecting the individual patient.

Early detection is needed because lifestyle modifications and strict control of metabolic risk factors are the most effective treatment. Because disease progression is typically slow, patients can be managed well by primary care physicians. NAFLD patients with 

 should be referred to specialist care for further assessment. 

While finding and managing fibrotic NASH is an important component to addressing liver disease, patients with steatosis alone are at a greater risk of cardiovascular mortality and morbidity.

Physicians should consider integrating non-invasive, point-of-care liver examinations as a way to improve patient intake, outcomes, lower costs and enhance income stream. FibroScan, for example, is an FDA cleared technology for the diagnosis and monitoring of adult patients as part of an overall evaluation of liver health.

Unlike blood tests that measure circulating markers of inflammation, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), this tool directly and non-invasively measures physical properties of stiffness and liver fat. 

It provides reproducible results, allowing for both diagnosis and monitoring of liver stiffness and liver fat, and has been recognized as a cost-effective tool for 

 in people with NAFLD. This information can support care management across key components of the metabolic syndrome – diabetes and hyperlipidemia.

When it comes to treating NAFLD, diet and exercise interventions are the first line of therapy, with the goal of decreasing body weight and modifying cardio-metabolic risk factors related to metabolic syndrome. In the early stages of NAFLD, a healthy diet and weight loss of at least 

 might be sufficient. Patients are often treated with vitamin E as well. Aggressive management of hypertension, diabetes and lipid disorder is also key.

San Diego-based La Maestra, a health center serving low-income and immigrant residents, has seen an alarming rise in liver disease. Because of this, every liver patient at La Maestra undergoes a rapid, non-invasive point of care examination, which validates that they have determined elastography with CAP to be an essential part of a patient’s workup, along with a full abdominal ultrasound that includes special liver cancer biomarkers, a liver panel that includes liver enzymes and liver function, chemistry panel and a CBC as well as APRI, FIB4 NAFLD score calculations.

La Maestra has found it to be particularly useful to share the patient’s liver health score and CAP with patients who have NAFLD to illustrate the change in liver fat and the need for adjusting their treatment and calculation of the FAST score.

Physician practices working in the community health center setting can play a significant role in helping to reverse the nation’s liver disease epidemic through early detection and monitoring of NAFLD/NASH. 

Ultimately, having a non-invasive tool at the point of care to examine liver health provides quantifiable information that can improve individual health outcomes, lower payer costs by avoiding expensive, invasive interventions and enhance the financial performance of a physician practice.

Robert Gish, MD

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