Crigler-Najjar syndrome is a condition caused by mutations in the hepatocyte enzyme UGT. In type I Crigler-Najjar syndrome, a congenital missense mutation leads to a complete lack of this enzyme. On the other hand, type II Crigler-Najjar syndrome patients have a milder mutation that reduces UGT levels to about 10% of those seen in normal individuals. This syndrome impairs the ability of hepatocytes to conjugate bilirubin to varying degrees of severity. Consequently, unconjugated bilirubin regurgitates back into the circulation and binds to albumin, posing a risk of neurological injury if levels rise rapidly. The only effective treatment for type I Crigler-Najjar syndrome currently is liver transplantation, although gene therapy may become a promising option in the future. Type II patients can sometimes be effectively managed with blue light, which converts circulating unconjugated bilirubin into more water-soluble forms that are less firmly bound to albumin, allowing for excretion in urine.

The liver plays a crucial role in preventing the accumulation of ammonia in the circulation, as it is highly toxic to the central nervous system, similar to bilirubin. Ammonia, a small neutral metabolite resulting from protein breakdown and bacterial activity, can easily permeate cell membranes. The liver eliminates ammonia by converting it into urea through a series of enzymatic reactions known as the urea cycle. This process occurs exclusively in the liver, making it the sole tissue capable of converting ammonia to urea.

Ammonia has two primary sources. Approximately 50% is produced by bacterial ureases in the colon. Some of the ammonia in the colonic lumen is converted to the impermeable ammonium ion (NH4+), allowing for its excretion in stool. However, the remaining ammonia crosses the colonic epithelium passively and enters the liver through the portal circulation. The kidney accounts for the other major source of ammonia (around 40%). A small portion (approximately 10%) is derived from amino acid deamination in the liver, metabolic processes in muscle cells, and the release of glutamine from senescent red blood cells.

The mass balance for ammonia handling in a healthy adult is illustrated in Fig. 32.15. Although ammonia can pass through cell membranes without specific transporters, certain membrane proteins, including aquaporins, can facilitate its transport. Regardless of the mechanism, the physicochemical properties of ammonia ensure its efficient extraction from the portal and systemic circulation (see Fig. 32.14 - The urea cycle).

If the liver's metabolic capacity is acutely compromised, coma and death can rapidly occur. In chronic liver disease, patients may experience a gradual decline in mental function known as hepatic encephalopathy, which is caused by the action of ammonia and other toxins that the liver cannot clear. The development of confusion, dementia, and ultimately coma in a patient with liver disease indicates significant progression, and if left untreated, these symptoms can be fatal.

Clinical assessment of liver function.
Crigler-Najjar syndrome isaconditionassociatedwithmutationsinthehepatocyteenzymeUGT.IntypeICrigler-Najjarsyndrome,acongenitalmissensemutationresultsincompletelackofthisenzyme,whereaspatientswithtypeIICrigler-NajjarsyndromehaveamildermutationthatreducesUGTlevelstoabout10%ofthoseseeninnormalindividuals.Thuswithvaryingdegreesofseverity,Crigler-Najjarsyndromeimpairstheabilityofhepatocytestoconjugatebilirubin.Theunconjugatedbilirubinregurgitatesbackintothecirculationandbindstoalbumin,withanassociatedriskofneurologicalinjuryiflevelsriseprecipitously.TheonlyeffectivetreatmentoftypeICrigler-Najjarsyndromeatpresentislivertransplantation,althoughgenetherapymaybeapromisingoptioninthenearfuture.ThosewithtypeIIdiseasecansometimesbemanagedeffectivelywithbluelight.Thisconvertscirculatingunconjugatedbilirubintoformsthataremorewatersolubleandthuslessfirmlyboundtoalbumin,whichcanbeexcretedinurine.
Ammonia Handling by the Liver
Ammonia (NH3) is a small neutral metabolite that arises from protein catabolism and bacterial activity and is highly membrane permeant. The liver is a critical contributor to prevention of ammonia accumulation in the circulation, which is important because like bilirubin, ammonia is toxic to the central nervous system. The liver eliminates ammonia from the body by converting it to urea via a series of enzymatic reactions known as the urea, or Krebs-Henseleit, cycle (Fig. 32.14 ). The liver is the only tissue in the body that can convert ammonia to urea.
Ammonia is derived from two major sources. Approximately 50% is produced in the colon by bacterial ureases. Because the colonic lumen is normally slightly acidic, some of this ammonia is converted to the ammonium ion (NH4 +), which renders it impermeant to the colonic epithelium and therefore allows it to be excreted in stool. However, the remainder of the ammonia generated crosses the colonic epithelium passively and is transported to the liver via the portal circulation. The other major source of ammonia (≈40%) is the kidney (see ). A small amount of ammonia (≈10%) is derived from deamination of amino acids in the liver, by metabolic processes in muscle cells, and via release of glutamine from senescent red blood cells.
The “mass balance” for ammonia handling in a healthy adult is presented in
Fig. 32.15 . As just noted, ammonia is a small neutral molecule that readily crosses cell membranes without the benefit of a specific transporter, although some membrane proteins transport ammonia, including certain aquaporins. Whatever the mechanism for transport, the physicochemical properties of ammonia ensure that it is efficiently extracted from portal and systemic circulation •Fig. 32.14 Theureacycle.ADP,adenosinediphosphate;ATP,adenosinetriphosphate.
If the metabolic capacity of the liver is compromised acutely, coma and death can rapidly ensue. In chronic liver disease, patients may experience a gradual decline in mental function that reflects the action of both ammonia and other toxins that cannot be cleared by the liver, in a condition known as hepatic encephalopathy. Development of confusion, dementia, and eventually coma in a patient with liver disease is evidence of significant progression, and these symptoms can prove fatal if left untreated.
Clinical Assessment of Liver Function