Rare but relevant: Genetic liver disease in the general medical setting

BackgroundMedical literature on the prevalence of genetic liver disease is lacking. In this study, we investigated the in-hospital healthcare and economic burden from genetic causes of non-alcoholic chronic liver disease (NACLD) and non-alcoholic liver cirrhosis (NALC) in the USA.MethodsData were abstracted from the National Inpatient Sample database between 2002 and 2014 using ICD9 codes for patients discharged with NACLD and NALC secondary to genetic diseases including alpha-1 antitrypsin deficiency (A1ATd), cystic fibrosis (CF), Wilson disease (WD), hereditary hemochromatosis (HHC), glycogen storage disease, and disorders of aromatic amino-acid metabolism (DAAAM).ResultsThroughout the study period, there were 19,332 discharges for NACLD associated with the six genetic diseases including 14,368 for NALC. There were $1.09 billion in hospital charges, 790 in-hospital deaths, and 955 liver transplants performed. Overall, A1ATd was associated with 8,983 (62.52%) hospitalizations for NALC followed by WD, CF, and HHC. The highest in-hospital mortality was seen with HHC. The greatest frequency of liver transplants was seen with DAAAM.ConclusionThe number of hospitalizations for genetic liver diseases continues to increase. With increased funding and directed research efforts, we can aim to improve medical treatments and the quality of life for patients at risk for liver deterioration.

Long-term Outcome for Wilson Disease: 85% Good

Hepatitides of unspecified etiology in children may be caused by genetic disorders. Its early detection can improve the patient management with understanding the pathogenesis, more accurately predicting the course, preventive examinations and prescribing specialized pathogenetic therapy in selected cases. However, currently there are no guidelines for the optimal diagnosis of such cases. The purpose of this research was to develop an algorithm for the differential diagnosis of hepatitides of unspecified etiology in children based on the identified clinical and genetic features of hereditary liver diseases. Materials and methods used: a single-center cohort retrospective study of 179 children with hepatitides of unspecified etiology aged 0 to 18 y/o was conducted. All patients had undergone genetic examination, based on the results of which the two groups were formed as follows: with and without genetic liver disease. Statistical analysis of the patients’ clinical, laboratory and instrumental examinations was aimed at identifying key markers for common hereditary liver diseases in different age groups as well as statistically significant differences in rare genetic reasons for hepatitis. Results: 27 different genetic liver diseases were identified in 101 (56.4%) with hepatitis of unspecified etiology. The most frequently detected diseases were Wilson's disease (41 or 40.6%), alpha-1 antitrypsin deficiency (A1AD or AATD) (9 or 8.9%) and Alagille syndrome (ALGS) (8 or 7.9%). Other hereditary pathologies occurred in isolated cases though its total incidence was nearly half of all cases (43 or 42.6%). In order to identify such cases, it is advisable to perform exome sequencing. In order to determine the indications for genetic examination, Authors have developed the mathematical model for assessing the risk of hereditary liver disease (ROC-AUC 0.787 with 95% CI: 0.696-0.877, sensitivity 69.8% with 95% CI: 57.7%-81.3%, specificity 79.2% with 95% CI: 72.3%-84.8%). Conclusion: Authors offer the suggested algorithm for differential diagnosis of hepatitides of unspecified etiology in children that includes, on the first place, the exclusion of the most common genetic liver diseases followed by exome sequencing in high-risk cases that in its turn is calculated using the developed mathematical model.

IntroductionIdentifying the underlying cause of liver disease is important, however in 5–30% of patients with cirrhosis no cause can be found, which is referred to as cryptogenic cirrhosis (CC). From...

PREVIEWThe most common and clinically important genetic diseases leading to liver dysfunction in adults are Wilson's disease, hereditary hemochromatosis, and alpha [-antitrypsin deficiency. Although advances in molecular biology have led to the identification and characterization of the genetic defects in these disorders, gene testing has its strengths and limitations. Drs Morrison and Kowdley review these disorders and discuss how recent advances may affect patient care.

20-Year-Old Man With Elevated Liver Tests

There are no permanent remedies for patients suffering from genetic liver diseases (GLDs) and liver cirrhosis (LC). In such cases, liver transplantation has resulted in improved quality of life, but it is not affordable by most patients. Therefore, a cost-effective, safe, and permanent cure for these diseases is desirable. Cell therapy seems an encouraging option for treatment of these liver diseases in the future. Animal experiments and clinical studies have demonstrated that, depending on the nature of the liver disease and the patient, autologous and/or allogeneic bone marrow (BM)-derived stem-cell therapy could be a promising treatment option. Although no clinical trials using BM-derived stem cells for treatment of GLD have yet been conducted, many phase I clinical trials have been conducted and a few such trials for the treatment of LC by use of autologous and/or allogeneic cells are in progress. Overall, the results of these trials are indicative of clinical benefits with no adverse effect on the patients. This review focuses on the current status of BM stem-cell therapy for treatment of GLD and LC in experimental animals and human subjects. It also proposes safer approaches to immune-regulation in allogeneic transplantation of cells.

Alpha-1-antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease and is a prototype of liver diseases caused by the pathologic accumulation of aggregated mutant alpha-1-antitrypsin Z (ATZ) within liver cells. In the case of ATD-associated liver disease, the resulting “gain-of-function” toxicity can lead to serious clinical manifestations, including cirrhosis and hepatocellular carcinoma. Currently, the only definitive therapy for ATD-associated liver disease is liver transplantation, but recent efforts have demonstrated the exciting potential for novel therapies that target disposal of the mutant protein aggregates by harnessing a cellular homeostasis mechanism called autophagy. In this review, we will summarize research advances on autophagy and genetic liver diseases. We will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease.

This chapter discusses three of the major inherited forms of liver disease (all autosomal recessive): hereditary haemochromatosis, Wilson’s disease, and alpha-1-antitrypsin deficiency. Hereditary haemochromatosis is characterized by excessive absorption of dietary iron, with a pathological increase in total body iron that accumulates in tissues and organs, disrupting their function. Wilson’s disease (hepatolenticular degeneration) is an autosomal recessive genetic disorder in which copper accumulates in tissues. Alpha-1-antitrypsin deficiency is characterized by reduced circulating levels of alpha-1-antitrypsin, a liver-derived protease inhibitor, and accumulation within the hepatocytes of the abnormal, poorly degraded protein; the consequent excessive activity of proteases such as elastase in pulmonary alveoli, unopposed by protease inhibitors, leads to emphysema, and the accumulation of alpha-1-antitrypsin in hepatocytes causes liver dysfunction.

Genetic Causes of Liver Disease: When to Suspect a Genetic Etiology, Initial Lab Testing, and the Basics of Management

Liver Transplantation for Liver Malignancies in Wilson’s Disease

Primary biliary cholangitis (PBC) is a rare and chronic autoimmune liver disease characterized by the progressive destruction of small intrahepatic bile ducts that may eventually lead to cirrhosis. PBC with features of autoimmune hepatitis (AIH) has rarely been reported in pediatric patients with genetic defects. We present the case of an adolescent with chromosome 14q24.1q24.2 deletion who was given the diagnosis of stage IV PBC with features of AIH. A 19-year-old male adolescent with multiple congenital abnormalities and an intellectual disability presented with abnormal liver enzymes levels and pruritus for more than 5 years. Laboratory examinations revealed elevated levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase. After the exclusion of viral hepatitis, alpha-1 antitrypsin deficiency, Wilson's disease, and other genetic cholestatic liver diseases by laboratory tests and whole exome sequencing, a liver biopsy was performed and stage IV PBC was diagnosed. Notably, features of AIH were also noted in the histopathological report, indicating the presence of PBC with AIH features. The patient responded well to a combination therapy of ursodeoxycholic acid and steroids. Array comparative genomic hybridization analysis performed to study the congenital abnormalities revealed a 3.89 Mb 14q24.1q24.2 deletion. PBC with AIH features has rarely been reported in an adolescent with a chromosomal abnormality. The present case can increase awareness for early-onset PBC and its possible correlation with chromosomal defects.

Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (≥ F2) (P < 0.001), severe fibrosis (≥ F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of ≥ F2, ≥ F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children.

The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire first by contacting Dr. Deepak Kamat at DKamat@med.wayne.edu. An 18-year-old male with a 3-year history of alcohol abuse is referred from a rehabilitation center for fever, nausea, and nonbloody diarrhea for 3 days. Six weeks ago, he enrolled in an alcohol rehabilitation program and stopped drinking alcohol. Three weeks later, he noticed yellowing of his eyes and skin, difficulty sleeping, and dyspnea. On examination, his temperature is 100.6°F (38.1°C), blood pressure is 99/62 mm Hg, pulse is 124 beats per minute, and respiratory rate is 24 breaths per minute. He is slow to answer questions. There is no asterixis. He appears thin and jaundiced with enlarged parotid glands. Decreased breath sounds are noted on the right. A tender, enlarged liver and mild abdominal distension are noted. Trace bilateral lower-extremity edema is present. No stigmata of chronic liver disease are found. Laboratory findings reveal the following: white blood cell count, 25,600/μL (25.6 × 109/L) (87% neutrophils); hemoglobin, 8.2 g/dL (82 g/L); mean corpuscular volume, 106 fL; platelets, 40 × 103/μL (40 × 109/L); sodium, 135 mEq/L (135 mmol/L); potassium, 3.5 mEq/L (3.5 mmol/L); chloride, 106 mEq/L (106 mmol/L); bicarbonate, 15 mEq/L (15 mmol/L); blood urea nitrogen, 24 mg/dL (8.6 mmol/L); creatinine, 1.01 mg/dL (89 μmol/L); glucose, 118 mg/dL (6.6 mmol/L); alkaline phosphatase, 182 U/L; aspartate aminotransferase (AST), 194 U/L; alanine aminotransferase (ALT), 71 U/L; total bilirubin, 11.8 mg/dL (201.8 μmol/L); direct bilirubin, 7.3 mg/dL (124.9 μmol/L); albumin, 2.7 g/dL (27 g/L); prothrombin time, 19.2 seconds; and international normalized ratio, 1.4. Ethanol and acetaminophen were not detected in the serum. A chest radiograph reveals a right pleural effusion …

Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases.