ISOLATED ALTERATIONS OF BIOCHEMICAL MARKERS OF LIVER DAMAGE in a seemingly healthy patient can present a challenge for the clinician. In this review we provide a guide to interpreting alterations to liver enzyme levels. The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed. Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.

/pdf/liver-enzyme-alteration-a-guide-for-clinicians-jxz9dbq4z2.pdf

Liver enzyme alteration: a guide for clinicians

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60439-5.pdf

Wilson's Disease

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22261

Diagnosis and treatment of Wilson disease: an update.

This Clinical Practice Guideline (CPG) has been developed to assist physicians and other healthcare providers in the diagnosis and management of patients with Wilson's disease. The goal is to describe a number of generally accepted approaches for diagnosis, prevention, and treatment of Wilson's disease. Recommendations are based on a systematic literature review in the Medline (PubMed version), Embase (Dialog version), and the Cochrane Library databases using entries from 1966 to 2011. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system used in other EASL CPGs was used and set against the somewhat different grading system used in the AASLD guidelines (Table 1A and B). Unfortunately, there is not a single randomized controlled trial conducted in Wilson's disease which has an optimal design. Thus, it is impossible to assign a high or even a moderate quality of evidence to any of the questions dealt with in these guidelines. The evaluation is mostly based on large case series which have been reported within the last decades.

EASL Clinical Practice Guidelines: Wilson's disease

Copper-transporting ATPases (Cu-ATPases) ATP7A and ATP7B are evolutionarily conserved polytopic membrane proteins with essential roles in human physiology. The Cu-ATPases are expressed in most tissues, and their transport activity is crucial for central nervous system development, liver function, connective tissue formation, and many other physiological processes. The loss of ATP7A or ATP7B function is associated with severe metabolic disorders, Menkes disease, and Wilson disease. In cells, the Cu-ATPases maintain intracellular copper concentration by transporting copper from the cytosol across cellular membranes. They also contribute to protein biosynthesis by delivering copper into the lumen of the secretory pathway where metal ion is incorporated into copper-dependent enzymes. The biosynthetic and homeostatic functions of Cu-ATPases are performed in different cell compartments; targeting to these compartments and the functional activity of Cu-ATPase are both regulated by copper. In recent years, significant progress has been made in understanding the structure, function, and regulation of these essential transporters. These studies raised many new questions related to specific physiological roles of Cu-ATPases in various tissues and complex mechanisms that control the Cu-ATPase function. This review summarizes current data on the structural organization and functional properties of ATP7A and ATP7B as well as their localization and functions in various tissues, and discusses the current models of regulated trafficking of human Cu-ATPases.

Function and Regulation of Human Copper-Transporting ATPases

Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non-neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) (1, 2). The Wilson disease gene ATP7B encodes a P-type ATPase. More than 200 disease causing mutations of this gene have been described so far (3). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian (4-6) or R778L in Japanese (7), Chinese and Korean patients). Studies of phenotype-genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16-18, 2001). After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.

Georgios Loudianos

Papers

Diagnosis and phenotypic classification of Wilson disease