CHAPTER 55
Metabolic diseases of the liver

Jacob Bilhartz and Frederick K. Askari

University of Michigan, Ann Arbor, MI, USA

Metabolic liver disease is a broad category of disorders with genetic roots that all contribute to the abnormal build‐up of toxic compounds or elements in the body. This build‐up can directly result in parenchymal liver disease with the typical complications of progressive liver fibrosis and end‐stage dysfunction in addition to any sequelae specific to the metabolic defect, or, in the case of diseases such as the urea cycle defects, Crigler–Najjar syndrome, and familial hypercholesterolemia, the toxic byproducts cause disease elsewhere without affecting liver function itself. In this chapter, we focus on those metabolic defects that result in parenchymal liver disease. While these diseases can progress to end‐stage liver disease, for many, there are treatments that can be successful at forestalling disease progression if started in a timely fashion. Thus, having a good understanding of their presentation and work‐up is critical for the practicing gastroenterologist.

Wilson disease

Wilson disease is a disorder of copper metabolism caused by mutations in the ATP7B gene which codes for a copper transporter protein predominantly expressed in hepatocytes and contributing to copper export. Defects in this protein cause a build‐up of copper inside the hepatocytes which leads to progressive liver fibrosis over time. Build‐up of copper in extrahepatic tissues, notably the neurological system, causes characteristic physical findings of Wilson disease such as the Kayser–Fleischer ring (Figure 55.1). Wilson disease comprises a wide clinical spectrum from asymptomatic hepatocellular inflammation, to cirrhosis and end‐stage liver disease. It can also cause acute liver failure. Diagnostic criteria for Wilson disease are reviewed in Table 55.1, but they are imperfect and scoring systems such as the Leipzig system can sometimes be useful (Table 55.2).

The treatment approach to Wilson disease consists of therapies that either prevent uptake of copper (zinc) or facilitate excretion (trientine). While Wilson disease presenting as acute liver failure typically requires liver transplantation, there are rare cases of recovery with aggressive medical treatment (Tables 55.3 and 55.4).

α1‐Antitrypsin deficiency

Mutations in the gene encoding the protease inhibitor α1‐antitrypsin result in a spectrum of clinical phenotypes. Those resulting in a pure deficiency of serum α1‐antitrypsin do not cause liver disease although they do increase the risk of obstructive pulmonary disease; this risk is dramatically increased by exposure to tobacco smoke. Mutations that lead to accumulation of abnormal α1‐antitrypsin inside hepatocytes are associated with varying presentations, including neonatal cholestasis and cirrhosis diagnosed later in life. There is currently no approved treatment for the hepatic manifestations of α1‐antitrypsin deficiency although studies of autophagy‐promoting drugs and gene therapy are ongoing. Liver transplantation relieves both the hepatic and extrahepatic manifestations of the disease by restoring normal serum levels of α1‐antitrypsin.

Porphyrias

There are eight human porphyrias, caused by deficiency or dysfunction of different enzymes involved in the heme biosynthesis pathway (Figure 55.2). These result in toxic accumulation of byproducts. Porphyrias have variable presentation (Table 55.5). Treatment is geared towards decreasing formation of toxic metabolites which reduces the hepatic and extrahepatic injury, although liver transplantation is sometimes required.

Photo depicts Kayser–Fleischer ring, brown copper deposition in the Desçemet membrane at the periphery of the cornea, best visualized on slit lamp examination. — **Figure 55.1** Kayser–Fleischer ring, brown copper deposition in the Desçemet membrane at the periphery of the cornea, best visualized on slit lamp examination.

Metabolic liver diseases presenting in infancy or early childhood

Our understanding of metabolic liver diseases which present very early in life is rapidly expanding as genetic diagnostic capabilities improve. Three conditions, which can now be detected on most newborn screening assays, are tyrosinemia, galactosemia, and hereditary fructose intolerance. Hepatic manifestations typically include neonatal cholestasis or liver failure. Treatment consists of restriction of precursors in the defective pathways (tyrosine/phenylalanine, galactose, and fructose), and administration of NTBC (2‐[2‐nitro‐4‐trifluoromethylbenzoyl]‐1,3‐cyclohexanedione) in the case of tyrosinemia which inhibits 4‐hydroxy phenyl‐pyruvate dioxygenase, the second enzyme in the tyrosine metabolism pathway.

Glycogen storage disorders

These disorders are a diverse group of conditions resulting from defects in glycogen metabolism (Figure 55.3). The clinical presentation is variable, but of particular note is type 1 which can result in the development of hepatocellular carcinoma even in the absence of significant fibrosis, and types 3 and 4 which are at risk for the development of progressive fibrosis and end‐stage chronic liver disease (Table 55.6). Treatment typically consists of dietary management aimed at avoiding hypoglycemia, although this is not effective at managing type 4 which does not have an effective treatment.

Mitochondrial hepatopathies and Reye syndrome

Mitochondrial dysfunction commonly affects the liver and can present in varied ways, including acute liver failure in infancy or more slowly progressive cholestasis and cirrhosis developing at an older age (Box 55.1). While mitochondrial liver disease is most common in early childhood, it can present at any age. Diagnosis is based on a combination of biochemical and genetic testing; liver histology is nonspecific but typically demonstrates widespread steatosis and necrosis. A lactate:pyruvate molar ratio of >20 is suggestive of a mitochondrial etiology. Treatment generally consists of supportive care although, for patients without any evidence of extrahepatic involvement, liver transplantation has been successful. Reye syndrome is included here primarily out of historical interest; described initially as acute liver failure developing in children given aspirin during the course of a viral infection, liver histology typically demonstrates abnormal mitochondria and steatosis. The diagnosis of Reye syndrome has decreased through avoidance of use of aspirin in children.

Table 55.1 Diagnostic tests for Wilson disease.

Diagnostic test	Diagnostic values	Causes of false positives	Causes of false negatives
Serum ceruloplasmin	<20 mg/dL	Kwashiorkor, nutritional copper deficiency, protein‐losing state, fulminant hepatitis, hepatic failure, hereditary hypoceruloplasminemia or aceruloplasminemia, Wilson disease, heterozygote, Menkes syndrome, normal neonate	Acute inflammation (hepatitis), malignancy, pregnancy or estrogen therapy in Wilson disease (5% of patients), immunoassays of apoceruloplasmin
Hepatic copper concentration	>250 μg/g dry weight	Primary biliary cirrhosis, Indian childhood cirrhosis, chronic cholestatic liver disease, primary sclerosing cholangitis, Alagille syndrome, liver tumors, newborn liver	Copper chelation therapy in Wilson disease
24‐h urine copper excretion	>100 μg/24 h	Copper chelation therapy, chronic active hepatitis, chronic cholestatic liver diseases, primary sclerosing cholangitis, hepatic failure, nephrotic syndrome	Copper chelation therapy in Wilson disease
Presence of Kayser–Fleischer rings	Present	Chronic cholestatic liver diseases, primary biliary cirrhosis, neonatal cholestasis	Early or hepatic Wilson disease
Incorporation of ⁶⁴Cu into ceruloplasmin	Low	Ceruloplasmin <20 mg/dL, Wilson disease heterozygote	Pregnancy, estrogens, inflammation or malignancy in Wilson disease
Genotyping for ATP7B	Two pathological mutations	Incorrectly assigning ATP7B polymorphisms or mutations of unknown significance which actually do not cause disease as pathogenic	Finding of only one pathogenic mutation; missing mutations of unknown significance which cause disease; pathogenic intronic mutations or gene regulatory mutations, splice site mutations that can be missed with current clinical genetic testing techniques

Table 55.2 Leipzig Scoring System. Disease symptoms are graded with points awarded based on score. If the total points are greater than 4, it is considered consistent with the diagnosis of Wilson disease. If 2 or fewer points, the diagnosis is unlikely. If the score is 3, further testing is indicated.

	Grading	Points awarded
Kayser–Fleischer rings	Present	2
	Absent	0
Neurological symptoms	Severe	2
	Mild	1
	Absent	0
Ceruloplasmin	Normal >0.2 g/L	0
	0.1–0.2 g/L	1
	<0.1 g/L	2
DAT‐negative hemolytic anemia	Present	1
	Absent	0
Liver copper (no cholestasis)	>5× upper limit normal	2
	>Normal <5× upper limit normal	1
	Normal	‐1
	Positive copper stain (only if no liver copper run)	1
24‐Hour urinary copper (no acute hepatitis)	>2× upper limit normal	2
	1–2× upper limit normal	1
	Normal	0
	Positive penicillamine challenge	2
Mutation analysis ATP7B	Two pathogenic mutations, both chromosomes	4
	One pathogenic mutation	1
	No pathogenic mutations	0

DAT, direct antiglobulin test.

Table 55.3 Treatment phases can be classified according to predominant symptoms, disease severity, and time on copper reduction treatment.

Wilson disease treatment phase	Generally preferred treatment
Acute liver failure (fulminant)	Plasmapheresis, liver transplantation
Initial treatment hepatic	Trientine or combined trientine and zinc
Initial treatment neurological	TTM (tetrathiomolybdate) in clinical trial, trientine or combination of trientine and zinc
Presymptomatic	Zinc or trientine
Maintenance	Zinc or trientine
Pregnancy	Zinc

Table 55.4 Urinary treatment monitoring targets. Twenty‐four hour urine collections can be monitored as a reflection of body copper stores and treatment efficacy, every 6–12 months if stable.

Copper reduction medication	Therapeutic 24‐hour urine copper target	Therapeutic 24‐hour urine zinc target
Zinc	40–75 μg/24 h ideal 50–125 μg/24 h in initial clinical trial	Generally greater than 2 mg/24 h
Trientine	24‐h urinary copper 200–400 μg/24 h if consistently taking chelation therapy
Penicillamine	24‐h urinary copper 200–400 μg/24 h if consistently taking chelation therapy

Schematic illustration of the heme synthesis pathway and location of the enzymatic defects responsible for the eight clinical porphyrias. — **Figure 55.2** The heme synthesis pathway and location of the enzymatic defects responsible for the eight clinical porphyrias.

Source: Stölzel U., Doss M., Schuppan D. Gastroenterology 2019;157:365. Reproduced with permission of Elsevier.

Table 55.5 Clinical and laboratory characteristics of the porphyrias.

Source: Stölzel U., Doss M., Schuppan D. Gastroenterology 2019;157:365. Reproduced with permission of Elsevier.

Porphyria and lead poisoning	Enzyme activities	Biochemical testing	Second‐line diagnostics	Plasma screen, nm ^a	Neurovisceral symptoms	Cutaneous symptoms	Anemia	Liver damage
AHPs
AIP	PBGD ↓	Urinary ALA ↑↑, PBG ↑↑, and porphyrins ↑↑	PBGD activity^b Mutation analysis	615–620	++	−	−	−/+
VP	PPOX ↓	Urinary ALA ↑↑, PBG ↑↑, and porphyrins ↑↑ Fecal PPIX ↑↑ and coproporphyrin III ↑	Mutation analysis	625–627	++	−/+	−	−/+
HCP^c	CPOX ↓	Urinary ALA ↑↑, PBG ↑↑, and porphyrins ↑↑ Fecal coproporphyrin III ↑	Mutation analysis	615–620	++	−/+	−	−/+
ALADP	ALAD ↓	Urinary ALA ↑↑ and PBG normal or ↑ and coproporphyrin isomer III ↑↑	ALAD activity Mutation analysis	615–619	++	−	−/+	−
Other hepatic porphyrias
PCT and HEP	UROD ↓	Urinary porphyrins ↑↑ Uro‐ and coproporphyrin^d	UROD activity ^eMutation analysis	615–620	− −	+ ++	− −/+	+ +
Erythropoietic porphyrias
EPP	FECH ↓	Erythrocyte metal‐free PPIX ↑↑ and Zn‐bound PPIX^f ↑	Mutation analysis	624–635	−	++	−/+	−/+
XLP	ALAS2 ↑	Erythrocyte metal‐free PPIX ↑↑ and Zn‐bound PPIX^g ↑↑	Mutation analysis	624–635	−	++	−/+	−/+
CEP	UROS ↓	Urinary and fecal uro‐ and coproporphyrin isomer I ↑↑	Mutation analysis	615–620	−	++	+	−
Other
Lead poisoning	ALAD ↓	Urinary ALA ↑↑ and PBG normal or ↑ and coproporphyrin isomer III ↑^h Erythrocyte metal‐free PPIX ↑ and Zn‐bound PPIX ↑↑	ALAD activity Lead concentration ↑↑ (blood, urine)	615–620	++	−	+	+

^a Fluorescence emission maximum (nm) of plasma porphyrins on excitation at 405 nm.

^b Decreased enzyme activity in blood, normal only in the nonerythroid splice site mutation variant.

^c A specific homozygous mutation or null allele of the CPOX gene leads to the phenotypically different rare harderoporphyria that lacks abdominal and neurological symptoms.

^d Increased fecal isocoproporphyrin is a sufficient but not necessary indicator of PCT/HEP; increased metal‐free and zinc‐bound protoporphyrin in erythrocytes is only found in HEP.

^e Decreased enzyme activity in blood; normal activity in blood only in acquired (type 1) PCT.

^f In EPP, the ratio of zinc‐bound protoporphyrin to metal‐free protoporphyrin is significantly lower (<15%) than in XLP.

^g In XLP, the ratio of zinc‐bound protoporphyrin to metal‐free protoporphyrin is >25%.

^h Lead poisoning affects three enzymes involved in heme biosynthesis (ALAD, CPOX, and FECH).

AHP, acute hepatic porphyria; AIP, acute intermittent porphyria; ALA, aminolevulinic acid; ALAD, aminolevulinic acid dehydratase; ALADP, aminolevulinic acid dehydratase porphyria, CEP, congenital erythropoietic porphyria; CPOX, copro‐oxidase; EPP, erythropoietic protoporphyria; FECH, ferrochelastase; HCP, hereditary coproporphyria; HEP, hepatoerythropoietic porphyria; PBG, porphobilinogen; PBGD, porphobilinogen deaminase; PCT, poprhyria cutanea tarda; PPIX, protoporphyrin IX; PPOX, protoporphyrinogen oxidase; UROD, uroporphyrinogen decarboxylase ; UROS, uroporphyrinogen III synthase ; VP, variegate porphyria ; XLP, X‐linked erythropoietic protoporphyria.

Schematic illustration of the glycogenolysis pathway and enzymatic defects involved in the glycogen storage disorders. — **Figure 55.3** The glycogenolysis pathway and enzymatic defects involved in the glycogen storage disorders.

Source: Kishnani P., Goldstein J., Austin S., et al. Genet Med 2019;21:772. Reproduced with permission of Springer Nature.

Table 55.6 Hepatic glycogen storage diseases (GSD).

GSD type	Enzyme defect	Clinical manifestations	Liver histology	Laboratory tests	Treatment
Ia	Glucose‐6‐phosphatase	Hepatic adenomas and HCC (no fibrosis), hypoglycemia, hepatomegaly, lactic acidosis, growth failure	Glycogen accumulation, macrovesicular steatosis	AST/ALT elevations, hypoglycemia, hyperlipidemia, lactic acidosis, hyperuricemia	Avoid hypoglycemia, frequent daytime and continuous overnight feeds, cornstarch in older infants and children
Ib	T1‐translocase	Hepatic adenomas and HCC (no fibrosis), hypoglycemia, hepatomegaly, lactic acidosis, neutropenia and infections, growth failure	Glycogen accumulation, macrovesicular steatosis	AST/ALT elevations, hypoglycemia, hyperlipidemia, lactic acidosis, hyperuricemia, neutropenia
III	Amylo‐1,6‐glucosidase “debrancher enzyme”	Variable hepatic fibrosis and portal hypertension, hypoglycemia, lactic acidosis, growth failure, hypotonia, cardiomyopathy	Glycogen accumulation, portal fibrosis	AST/ALT elevations; variable hyperlipidemia, hypoglycemia, lactic acidosis, hyperuricemia	Avoid hypoglycemia, frequent feeds, may need continuous feeds or cornstarch, high‐protein diet after 6 months
IV	Amylo‐1,4→1,6‐transglucosidase “brancher” enzyme	Jaundice, hepatosplenomegaly, liver failure, portal hypertension, hypotonia	Glycogen accumulation, cirrhosis, PAS‐positive storage material	AST/ALT elevations, coagulopathy, conjugated hyperbilirubinemia, hypoglycemia, hyopalbuminemia	Dietary management not affective at halting disease progression
VI	Liver phosphorylase	Hepatomegaly	Glycogen accumulation	AST/ALT elevations	Avoid hypoglycemia, frequent feeds, may need cornstarch
IX	Liver phosphorylase‐b‐kinase	Hepatomegaly, rarely portal hypertension	Glycogen accumulation, variable fibrosis	AST/ALT elevations	Avoid hypoglycemia, frequent feeds, may need cornstarch