PEDIATRIC PUZZLER

GEORGE K. SIBERRY, MD, MPH, SECTION EDITOR

Bloody emesis after epistaxis at 9 years old:
A penny for your thoughts!

By Lily C. Chao, MD, and Sue V. McDiarmid, MD

The occasion is a Friday afternoon and the setting is your general pediatrics practice, where your next patient is a 9-year-old boy who has been brought in by his parents because of recurrent nosebleeds. You determine that his vital signs are stable and proceed to take a history. The parents report that their son has had five or six episodes of heavy nosebleed during the past month. They describe the bleeding as spontaneous, not limited to one nostril, and, typically, stopping after pressure was applied to the nasal septum for 15 minutes. The boy denies bleeding of the gums, easy bruising, or hematemesis. He has a history of allergic rhinitis, but the medical history is otherwise unremarkable. The family history is unrevealing for bleeding disorders or neurologic or hepatic ailments. The patient has a 7-year-old sister who is healthy. His immunizations are up to date.

Your initial physical examination reveals an apprehensive but cooperative child. Some dried blood clot can be seen over the right anterior-inferior septum, although there is no active bleeding. You don't see any intranasal mass or septum deviation. There are otherwise no objective signs of excessive blood loss—no conjunctival pallor, no tachycardia, no hypotension. A careful skin exam does not reveal petechiae, bruising, or other vascular malformations. No hepatosplenomegaly is appreciated.

"And laying his finger aside of his nose"

What can cause recurrent epistaxis in a child? Usually, digital trauma, which your patient denies. Local inflammation, secondary to dry cold air, upper respiratory tract infection, sinusitis, or allergic rhinitis, can all produce epistaxis. Primary bleeding disorders, such as thrombocytopenia, von Willebrand disease, and other deficiencies of clotting factors, can also cause recurrent epistaxis. Systemic disturbances, such as hypertension and renal disease, should be included in the differential diagnosis. Although congenital vascular abnormalities such as hereditary hemorrhagic telangiectasias are rare, they should be considered when there is severe recurrent epistaxis—although the absence of a bleeding disorder in the family and of telangiectasias make that diagnosis less likely in this patient. Last, any sort of intranasal tumor, such as juvenile nasal angiofibroma, can cause recurrent nosebleeds.

This boy's history of allergic rhinitis can certainly explain the frequency of epistaxis, although their duration seems unusual. He is normotensive and shows no systemic signs of renal failure. To exclude a primary bleeding disorder, you order a complete blood count and tests of the prothrombin time (PT) and activated partial thromboplastin time (aPTT). Assays of factor VIII, factor IX, factor VIII antigen, and von Willebrand factor, and multimer analysis, are ordered to evaluate for factor VIII and factor IX deficiency and von Willebrand disease. Except for mild elevation of PT (13 sec) and a borderline-low level of factor IX, lab studies are normal.

For now, you refer the child to the pediatric otolaryngologist for possible cauterization and decide to follow him clinically. Over the next few months, after cauterization, his parents report no recurrence of epistaxis.

Nose is not news, now emesis is

Six months later, however, the boy and his parents return to your office. He has had intermittent nonbilious and, until today, nonbloody vomiting for the past month that is not associated with eating and that seems to occur more often in the morning. He has also been having vague abdominal pain and feeling more tired lately, they tell you, and, before lunch today, he vomited again, producing a small amount of frank blood. Upon questioning, he denies any nausea or abdominal pain at the moment, or having black stools. He has no recent history of retching, respiratory illness, weight loss, or fever. And, as you know, he also has not had any more episodes of epistaxis.

The physical examination this day is remarkable on several counts. The boy's complexion and conjunctiva are pale without scleral icterus. You do not detect blood in the nose, mouth, or pharynx, or any rashes or petechiae. You appreciate a palpable liver edge 1 or 2 cm below the right costal margin. The spleen tip is palpable 1 cm below the left costal margin. There is no abdominal distension or tenderness to palpation. No caput medusa is visible.

What's the differential?

A history of recurrent epistaxis and, now, hematemesis brings you back to the possibility of a coagulopathy. Add the physical findings of hepatosplenomegaly and anemia to what you know, and liver dysfunction with secondary deficiency of a clotting factor rises to the top of your differential; a primary hematologic disorder with extramedullary erythropoiesis can also explain the signs and symptoms.

You order preliminary lab tests to help direct the differential. A CBC shows a normal white blood cell count and differential count. Hematocrit is 28%; platelet count, 320 x 10³/µL; PT, now 36, with an International Normalized Ratio (INR) of 3.6; and aPTT, 48. Electrolyte levels are unremarkable, except for a non-anion gap acidosis; bicarbonate, 16 mmol/L; and phosphorus, 2.3 mg/dL. Liver function tests reveal the following: alanine aminotrasferase, 267 U/L; aspartate aminotransferase, 383 U/L; and total bilirubin, 1.5 mg/dL (conjugated bilirubin, 0.4 mg/dL). The uric acid level is 0.3 mg/dL; albumin, 2.2 g/dL; alkaline phosphatase, 324 U/L. Routine urinalysis reveals a pH of 7.0; 1+ blood; and 3+ glycosuria.

Over the next 72 hours, the patient develops signs of hemolytic anemia, with a hematocrit of 23% and total bilirubin of 3.6 mg/dL (conjugated bilirubin, 0.8 mg/dL). Alarmingly, fresh frozen plasma (20 mL/kg of body weight) and vitamin K do not correct his prolonged INR.

Poor synthetic function and elevated levels of transaminases—these findings point to liver disease. Acute hepatitis is a possibility; you must also consider hepatitis A, B, and C, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection, toxins, and drugs. But the profound coagulopathy in the face of a low albumin level suggests chronic liver disease (especially with a history of mild coagulopathy in the past).

What, then, can cause chronic liver disease in a 9-year-old? Chronic hepatitis B and C should be tested for, but you realize that these are unlikely culprits without other risk factors.

In the absence of an obvious cause for the child's problems, metabolic disorders such as a₁-antitrypsin deficiency—the most common genetic cause of cirrhosis in children—and Wilson disease should be considered. Autoimmune hepatitis can also cause chronic liver disease. Tyrosinemia type 1—particularly in patients of Scandinavian descent or who are Québeçois—is also in the differential diagnosis, although onset this late in life would be unusual. Gaucher disease, glycogen storage disease, and cystic fibrosis should be considered even though they are highly unlikely in the absence of other associated clinical features.

To sort out these possibilities, you send off blood for more studies—to begin, antigen tests, serologic studies, and DNA polymerase chain reaction assays for viral hepatitis. Results come back normal (as do serologic studies of EBV, CMV, hepatitis B and C); you move on to metabolic causes. A₁-antitrypsin activity is normal. Evaluation for tyrosinemia is unconvincing—a-fetoprotein is mildly elevated at 27 ng/mL (normal, 0 to 6.7 ng/mL) and the urine succinylacetone level is normal. The autoimmune workup is negative except for an elevated dsDNA autoantibody level. Serum copper and ceruloplasmin levels (the latter measured by immunoassay) are normal: 45 mg/dL (normal, 17 to 41 mg/dL), and 119 µg/dL (normal, 67 to 147 µg/dL), respectively.

With the diagnosis still elusive, you decide to proceed with a transjugular liver biopsy (after infusing the patient with multiple units of fresh frozen plasma to bring his INR down to 1.5) to look for microscopic clues to the differential diagnosis of chronic liver disease. Analysis of the biopsy shows submassive parenchymal loss, microsteatosis, macrosteatosis, and cirrhosis.

As you try to sort through the differential diagnosis of this liver pathology, the lab calls: The 24-hour urine copper level is 2,085 µg (normal, 3 to 35 µg), and the liver copper content is 527 µg/g (normal, 10 to 35 µg/g). These findings confirm the diagnosis: Wilson disease.

Meanwhile, the patient's clinical status deteriorates rapidly, with increasing sleepiness and irritability and rising hyperammonemia. Because he is approaching fulminant hepatic failure so rapidly, with irreversible coagulopathy and persistent intravascular hemolysis, he is urgently placed on the liver transplant list. Ten days after the diagnosis of Wilson disease, he receives an orthotopic liver transplant. Afterward, the coagulopathy, hemolytic anemia, and renal tubular acidosis all resolve.

No route out for copper

First described in 1913 by Rumpel, Wilson disease is a rare, autosomal recessive disease with an incidence of one in every 30,000 people.¹ The defective gene, ATP7B, located on chromosome 13, is an ATPase that transports copper. Patients with Wilson disease carry two different mutated alleles, one on each chromosome, rendering their genetic defect as compound heterozygotic.

In a healthy person, dietary copper is absorbed via the upper small intestine into the portal circulation. After hepatic extraction for cellular functions, copper is excreted primarily through biliary drainage but is also released into the systemic circulation as ceruloplasmin-bound copper. The ATP7B gene is involved in both steps. With copper transport defective in Wilson disease, copper begins to accumulate in the liver and, subsequently, in the central nervous system and kidneys. Excess copper causes oxidative damage to cell membranes and DNA after the chelating and reducing capacities of intracellular glutathione and metallothionein are saturated.¹ Signs and symptoms of liver failure and neurologic and renal illness ensue.

Synthetic diagnosis

The age of onset of Wilson disease varies—from 5 to 50 years of age. It can manifest as acute hepatitis, chronic hepatitis with or without cirrhosis, fulminant liver failure, or primarily central nervous system disturbances, such as movement disorders, depression, and psychosis.² Direct or slit-lamp examination may reveal Kayser-Fleischer rings, which reflect copper deposition in the Descemet's membrane; 50% of people who have only liver disease—as is the case with most pediatric patients—do not have Kayser-Fleischer rings, however.³ Other nonspecific but suggestive signs of Wilson disease are non-immune hemolytic anemia and Fanconi renal tubular acidosis.

For lack of a pathognomonic test, the diagnosis of Wilson disease is made by synthesizing information from the medical and family history and physical exam, biochemical and histochemical test results, and, often, liver biopsy findings. When neurologic symptoms are present, Kayser-Fleischer rings are highly suggestive of Wilson disease, although their absence is not exclusionary.

Low serum levels of copper and ceruloplasmin, an elevated 24-hour urine copper level, and increased liver copper content are classic findings in Wilson disease. But—as this case illustrates—too much reliance placed on these tests can be a pitfall in making the diagnosis. The serum copper level may be normal or elevated in the face of acute liver decompensation, as copper is released from injured hepatocytes. Likewise, 5% to 10% of patients have a normal level of ceruloplasmin, because it is an acute-phase reactant that becomes elevated in the presence of chronic inflammation. The ceruloplasmin level can also be falsely elevated if—as was the case in this patient—it is measured by an immunologic assay that also detects apoceruloplasmin rather than oxidase activity.¹

In situations of borderline urine copper content, some authorities have proposed a penicillamine challenge, which enhances copper elimination in these patients, clarifying the diagnosis.⁴ Concomitant presence of Coombs-negative hemolytic anemia or Fanconi's renal tubular acidosis (evidenced by non-anion gap acidosis, hypophosphatemia accompanied by phosphaturia, and glycosuria), or both, should also raise the index of suspicion for this disease. Ultimately, as the extent of the coagulopathy permits, liver biopsy (for histologic study, staining for copper, and quantitation of copper [>250 µg/g]) provides the best chance of a definitive diagnosis.

When Wilson disease is diagnosed before the onset of cirrhosis, first-line treatment is copper-chelating agents, such as d-penicillamine, trientine, and tetrathiomolybdate—the choice depending on tolerance of reported adverse effects. Zinc has also been used successfully in children,⁵ indirectly reducing copper absorption by inducing synthesis of metallothionein in enterocytes, which preferentially binds copper, thereby blocking its absorption from the diet.³

With appropriate pharmacotherapy, hepatic and neurologic dysfunction and KF rings can be reversed. Patients who remain adherent can lead a normal, healthy life. In the setting of end-stage liver disease (because of late diagnosis or nonadherence), liver transplant may be lifesaving; in one series of 21 patients, one-year survival of 87.5% was reported.⁶

Last, siblings of patients must be screened for Wilson disease—initially, with tests of liver function, serum copper and ceruloplasmin, and 24-hour urinary copper content. Haplotype analysis of the patient and his or her parents may be used to determine whether a sibling has inherited the defective copies of ATP7B. In an asymptomatic sibling given a diagnosis of Wilson disease, prompt initiation of a chelating agent may be lifesaving.

A penny for our thoughts? When you confront a presentation of liver disease—acute or chronic—in a child, remember to place Wilson disease in the differential.

REFERENCES

1. Sternlieb I: Hepatology: A century of progress—Wilson's disease. Clin Liver Dis 2000;4:229

2. Cox DW, Roberts EA: Wilson disease, in Feldman M, Scharschmidt BF, Sleisenger M, et al (eds): Sleisenger Fordtran's Gastrointestinal and Liver Disease, ed 6, Philadelphia, Pa., WB Saunders, 1998, p 1104

3. Schilsky ML: Diagnosis and treatment of Wilson's disease. Pediatr Transplant 2002;6:15

4. Martins da Costa C, Baldwin D, Portmann B, et al: Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease. Hepatology 1992;15:609

5. Brewer GJ, Dick RD, Johnson VD, et al: Treatment of Wilson's disease with zinc XVI: Treatment during the pediatric years. J Lab Clin Med 2002;137:191

6. Schilsky ML: Treatment of Wilson disease: What are the relative roles of penicillamine, trientine and zinc supplementation? Curr Gastroenterol Rep 2001;3:5

DR. CHAO is a resident in the department of pediatrics at Mattel Children's Hospital, The David Geffen School of Medicine, University of California at Los Angeles.

DR. McDIARMID is professor of pediatrics and surgery at The David Geffen School of Medicine, University of California at Los Angeles.

DR. SIBERRY is an assistant professor of pediatrics in the divisions of general pediatric and adolescent medicine and pediatric infectious diseases at The Johns Hopkins Hospital.

 

Lily Chao, Sue McDiarmid. Pediatric Puzzler: Epistaxis in a nine-year-old. Contemporary Pediatrics December 2003;20:18.