Alpha-1 antitrypsin deficiency-associated comorbidities: Panniculitis & Co.

Alpha1 Germany eV.

Alpha-1 antitrypsin deficiency in newborns and children

Newborns and children with the PiZZ genotype frequently have liver involvement; approximately 10-15 individuals with % develop liver disease, and 1-5 develop cirrhosis. The cause is the altered structure of the pathological AAT. The PiZZ molecules clump together into long strands and are so large that they cannot be properly eliminated from the liver cells. The remaining AAT molecules are only gradually broken down. In contrast, lung involvement in children is extremely rare. In Sweden in the 1970s, researchers screened more than 200,000 newborns for AAT deficiency. They found the PiZZ genotype in 127 infants. At six months of age, 60 of these children with % had elevated liver enzyme levels in their blood. Two children died due to severe liver dysfunction. The results of a follow-up examination 26 years later were encouraging: all the adults were healthy, including those who had had liver involvement as children. Only 12% of the adults had abnormal liver values, but none of them had corresponding symptoms.

Rare manifestations in adults

Most individuals with the PiZZ type develop lung disease as adults. Progressive pulmonary emphysema and early-onset COPD are typical. Liver involvement is also not uncommon: the lifetime risk of liver cirrhosis is estimated at 30-40, and approximately 3 in % of patients even develop liver cancer. Therefore, early detection of liver involvement through regular examinations is crucial. In deceased individuals with AAT deficiency, pulmonary emphysema predominates at 72, followed by liver cirrhosis at 10. Other conditions, such as panniculitis or a specific inflammation of the blood vessels called C-ANCA-positive vasculitis, are rarely found.

Case report of a woman with panniculitis

A woman in her late forties from a neighboring country first presented herself at the Alpha1 Center in Münster in August 2011. She sought contact with the German experts because the health insurance companies in her home country refused to reimburse her for substitution therapy with Prolastin®.

Until the onset of her illness in 2008, the patient had been healthy, a non-smoker, and physically active. She was aware that she had a PiZZ genotype, as did one of her sisters. In 2008, coinciding with a stressful work situation, she experienced pronounced swelling of her limbs and gained a significant amount of weight, increasing by 25 kg in just a few weeks. She also had pronounced skin changes, and some lesions were oozing clear fluid.

The doctors diagnosed panniculitis. The patient was treated with various medications, primarily cortisone, several antibiotics, and a drug for leprosy. Despite this, her symptoms barely improved. In 2010, a panniculitis lesion above the coccyx became so severely inflamed and infected that surgery was necessary. Afterward, the patient had to remain on bed rest for two months. Doctors at two university hospitals did not consider AAT substitution absolutely necessary. Instead, they suggested a liver transplant.

Since she was unable to make progress in her home country, the patient sought treatment in Germany. At the initial examination in Münster, the patient was in poor condition, complaining of severe pain despite taking painkillers and psychotropic medications. She was 180 cm tall and weighed 132 kg. The skin manifestations of panniculitis were pronounced, as were the swelling and fluid retention in her torso and limbs. Inflammatory swelling with arthritis was observed in her hands and fingers. Pulmonary function testing showed a reduced FEV1 of only 51 TpF (1/3 Tcp) of predicted and marked diffusion impairment. Blood gas analysis revealed decreased oxygen levels and elevated pCO2. Her liver function tests were abnormal, consistent with chronic hepatitis.

For the doctors in Münster, there was no doubt that substitution with Prolastin® was urgently needed. After a six-month battle with the Dutch health insurance companies, the patient was finally able to begin treatment with AAT. Her AAT blood levels only reached the desired range once the Prolastin® dose was increased to 100 mg/kg body weight. Afterward, the patient's symptoms improved, but did not disappear completely. Significant weight fluctuations from day to day, sometimes as much as 4 kg, were particularly noticeable. The panniculitis was especially painful in the lumbar spine. Local anesthetics and anti-inflammatory steroids were injected there, which led to an improvement in her symptoms.

Doctors still don't fully understand the disease process in panniculitis. The optimal dose and duration of replacement therapy also remain unclear.

Case report of a man with normal FEV1

The man, in his mid-50s, had been diagnosed with AAT deficiency since 2013. The following year, he presented for the first time in Münster. The question was whether and how he could undergo replacement therapy despite good lung function. The patient had previously been largely healthy, although he had an unhealthy lifestyle including smoking and being overweight. One of his siblings had died from liver disease. Now the patient complained of shortness of breath at rest and during exertion. Pulmonary function tests showed a normal FEV1 of more than 120 Tp3T of predicted. However, there was impaired diffusion capacity, and the blood gases indicated hypoxia. A CT scan of the lungs revealed pulmonary emphysema. Examination of the liver showed early signs of cirrhosis.

Doctors in Münster determined from comparative data that the patient's FEV1 had deteriorated by 600 ml within a year and a half, even though it was currently still within the normal range. According to medical guidelines, this indicated the need for replacement therapy. A time-limited course of replacement therapy was chosen. After just a few infusions of AAT, the patient benefited from the treatment. His shortness of breath improved, and his blood oxygen levels increased. He will continue to be closely monitored even after the planned completion of the replacement therapy.

Despite a normal FEV1, this patient had a documented rapid decline in lung function. He also had symptoms. Therefore, the criteria for Prolastin® treatment were met, as specified in the drug's approval and the medical treatment guidelines.